Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:35]=[CH:34][C:26]([CH2:27][NH:28][C:29](=[O:33])[O:30][CH2:31]Cl)=[CH:25][CH:24]=1)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[P:36]([O:41]C)([O:39][CH3:40])[O:37][CH3:38]>ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:35]=[CH:34][C:26]([CH2:27][NH:28][C:29]([O:30][CH2:31][P:36](=[O:41])([O:39][CH3:40])[O:37][CH3:38])=[O:33])=[CH:25][CH:24]=1)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COP(OC)OC
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CNC(=O)OCCl)cc1
Solvent: ClCCl
Product: COP(=O)(COC(=O)NCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1)OC
Temperature: 100 °C

Procedure:
Chloromethyl [4-({[2-[(tert-butoxycarbonyl)amino]-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]carbamate (0.96 g, 1.860 mmol) and trimethyl phosphite (1 ml, 8.48 mmol) were combined in a microwave vial. The vial was capped and the reaction was allowed to heat for 3.5 hours at 100° C. The reaction was cooled and diluted with dichloromethane. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexane. MS: calc'd 490 (MH+-Boc), exp 490 (MH+-Boc).
Reaction SMILES: [CH2:1]([C:5]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)([CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:6]#[N:7])[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)[OH:22]>[OH-].[NH4+]>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:5]([CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([NH2:7])=[O:22])=[CH:19][CH:18]=1
Reactant: CCCCC(C#N)(Cn1cncn1)c1ccc(Cl)cc1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCCCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 168 h
Yield: 56.5 %

Procedure:
To a 500 mL flask was charged 75.0 g (0.24 mole) of alpha-n-butyl-alpha(4-chlorophenyl)-1H-1,2,4-triazole-1-propanenitrile followed by 300 mL of 95% sulfuric acid. The mixture was stirred at 90° C. for 7 days after which the mixture was cooled to room temperature, diluted with ice and neutralized with ammonium hydroxide until basic (pH 8). The product was extracted with ethylene dichloride then washed with water and dried over magnesium sulfate. The solvent was concentrated and gave 45 g (56.5% yield) of a solid melting point 197°-199° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([C@H:22]([NH2:24])[CH3:23])[CH:19]=[CH:20][CH:21]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36](=[O:37])[CH2:35][CH:34]([CH:38]=O)[CH2:33]2)=[CH:28][CH:27]=1>CC(O)=O.ClCCCl>[Cl:15][C:16]1[CH:17]=[C:18]([C@H:22]([NH:24][CH2:38][CH:34]2[CH2:33][N:32]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)[C:36](=[O:37])[CH2:35]2)[CH3:23])[CH:19]=[CH:20][CH:21]=1
Reactant: C[C@@H](N)c1cccc(Cl)c1
Reactant: O=CC1CC(=O)N(c2ccc(F)cc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C[C@@H](NCC1CC(=O)N(c2ccc(F)cc2)C1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20 mL vial was charged with sodium triacetoxyborohydride (1.0 g, 4.8 mmol), (R)-1-(3-chlorophenyl)ethanamine 55 (0.413 g, 2.7 mmol), 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carbaldehyde 54 (0.500 g, 2.4 mmol), 10 mL of DCE, and 5 drops of AcOH. This mixture was stirred at room temperature overnight then quenched with saturated aqueous NaHCO3. The mixture was extracted with DCM, dried, concentrated, and purified by column chromatography on silica gel (3% to 7% MeOH in DCM) to give 4-({[(1R)-1-(3-chlorophenyl)ethyl]amino}methyl)-1-(4-fluorophenyl)pyrrolidin-2-one 56 as a 1:1 mixture of diastereomers. Mass spectrum: calculated for C19H20ClFN2O 346.1; found 347.2 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:13]([O-])=O.[H-].[Na+].[CH3:18]I.O>CN(C)C=O>[NH2:13][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[CH3:1])[N:9]([CH3:18])[C:8](=[O:12])[CH2:7][CH2:6]2
Reactant: CI
Reactant: Cc1cc2c(cc1[N+](=O)[O-])CCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1N)CCC(=O)N2C
Yield: 60.9 %

Procedure:
The compound (3.14 g, 15.2 mmol) obtained in step A was dissolved in N,N-dimethylformamide (30 ml), 60% sodium hydride (730 mg, 18.2 mmol) was added under ice-cooling with stirring, and thereafter the mixture was stirred at room temperature for 30 min. The reaction mixture was ice-cooled again, methyl iodide (1.9 ml, 30.4 mmol) was added with stirring, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give a bistered solid. Using this solid and according to the method of Reference Example 116, step B, the title compound (1.76 g, yield 61%) was obtained as a pale-bistered solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC1(C)C(C)(C)OB([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]([F:52])([F:51])[F:50])O1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=5[C:49]([F:52])([F:51])[F:50])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: CC1(C)OB(c2ccccc2C(F)(F)F)OC1(C)C
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5C(F)(F)F)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 4,4,5,5-tetramethyl-2-(2-trifluoromethyl-phenyl)-[1,3,2]dioxaborolane.
Reaction SMILES: [Cl-:1].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O>C1(C)C(C)=CC=CC=1>[Br:28][C:29]1[CH:30]=[C:31]([CH:32]=[CH:8][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][Cl:1])[CH:34]=[CH:35][CH:36]=1
Reactant: [Cl-]
Reactant: C(=C1CCCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Br)c1
Solvent: Cc1ccccc1C
Product: O=C(C=Cc1cccc(Br)c1)CCCCCl
Temperature: 25 °C

Procedure:
2 parts of [(tetrahydro-2H-pyran-2-ylidene)methyl] triphenylphosphonium chloride and 1.85 parts of 3-bromobenzaldehyde were combined in 45 parts of xylene. This was maintained under a nitrogen atmosphere and was refluxed for 3 hours. After the reaction mixture was cooled to room temperature, xylene was removed at a temperature of about 60° C. and under reduced pressure, leaving a product mixture. This mixture was separated chromatographically on a silica column using benzene as the elution solvent, to yield 1-(3-bromophenyl)-7-chloro-1-hepten-3-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=O)[N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[NH2:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:14])[N:3]=1
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)c2ccnc-2[nH]1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
2-Aminopyrrolo[2,3-d]pyrimidin-4-one (45 g) was suspended in phosphorus oxychloride (150 ml) and the suspension was stirred at 110° C. for 3 hours. The excess amount of phosphorus oxychloride was distilled off under reduced pressure and ice water (600 ml) was added to the residue, whereby the residue was thoroughly dissolved. The solution was cooled with stirring and adjusted to pH 9 with concentrated aqueous ammonia. The resulting precipitate was collected by filtration, washed with water and recrystallized from hot methanol (4 l) to give the above-identified compound (34.6 g).
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>CC(C)=O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:20])=[CH:14][CH:13]=1
Reactant: CCCCC(=N)N
Reactant: COc1ccc(N=C=O)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccc(OC)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 3.39 g. sodium in 200 ml. dry acetone, 20 g. valeramidine hydrochloride and 21.9 g. 4-methoxyphenyl isocyanate in 100 ml. dry acetone, there ws obtained after recrystallization from ethyl alcohol 15.5 g. of the hydrochloride of 1-(4-methoxyphenyl)-3-(pentanimidoyl)urea; m.p. 143.5°-145°C.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C@H:10]1[C:15]1[NH:16][CH:17]=[C:18]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([C:36]4[N:37]=[C:38]([C@@H:41]5[CH2:45][C@H:44]([CH3:46])[CH2:43][N:42]5C(OC(C)(C)C)=O)[NH:39][CH:40]=4)=[CH:32][CH:31]=2)[CH:24]=[CH:23]3)[N:19]=1)=O)(C)(C)C>O1CCOCC1.CO>[CH3:46][C@@H:44]1[CH2:43][NH:42][C@H:41]([C:38]2[NH:39][CH:40]=[C:36]([C:33]3[CH:34]=[CH:35][C:30]([C:25]4[CH:24]=[CH:23][C:22]5[C:27](=[CH:28][CH:29]=[C:20]([C:18]6[N:19]=[C:15]([C@@H:10]7[CH2:11][C@H:12]([CH3:14])[CH2:13][NH:9]7)[NH:16][CH:17]=6)[CH:21]=5)[CH:26]=4)=[CH:31][CH:32]=3)[N:37]=2)[CH2:45]1
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7C[C@H](C)CN7C(=O)OC(C)(C)C)n6)ccc5c4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H]1CN[C@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7C[C@H](C)CN7)n6)ccc5c4)cc3)c[nH]2)C1
Reaction time: 2 h

Procedure:
A solution of 4N HCl in dioxane (15 mL) was added to tert-butyl(2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinecarboxylate (200 mg. 0.285 mmol) in MeOH (5 mL) and stirred at ambient conditions for 2 hours, concentrated, and dried under vacuum. Tetra HCl salt (assume theoretical: 185 mg). LC-MS retention time 2.64 min; Calcd. for C32H35N6: 503.29 m/z Found 503.20 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[S:13][CH2:14][C:15]#[N:16]>CCO.Cl>[NH2:16][C:15]1[CH2:14][S:13][C:3]2[CH:4]=[C:5]([O:8][C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: N#CCSc1cc(OC(F)(F)F)ccc1N
Agent: Cl
Solvent: CCO
Product: NC1=Nc2ccc(OC(F)(F)F)cc2SC1
Yield: 64.3 %

Procedure:
A solution of 2-[2-amino-5-(trifluoromethoxy)phenylthio]-acetonitrile (0.70 g, 2.82 mmol) in 5% EtOH/HCl (20 ml) is refluxed for 2 hours. The solvent is then evaporated under vacuum and the residue diluted with H2O. The resulting aqueous solution is washed with CHCl3, basified with conc. NH4OH and the precipitate extracted with CHCl3. The combined organic extracts are dried over Na2SO4 and concentrated to give the product as a pale yellow solid (0.45 g, 64% yield, m.p. 94-96° C.). 1H-NMR (CDCl3): 3.14 (s, 2H), 5.04 (br s, 2H), 6.92-7.10 (m, 3H). MS (ESI): m/z 249 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[C:13]1([NH:19][C:20](=[S:23])[NH:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5](=[N:22][NH:21][C:20](=[S:23])[NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NNC(=S)Nc1ccccc1
Reactant: O=C(CCCCl)c1ccccc1
Solvent: CCO
Product: S=C(NN=C(CCCCl)c1ccccc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 62.6 %

Procedure:
A mixture of 4-chlorobutyrophenone (6.7 mL, 42 mmol) and 4-phenyl-3-thiosemicarbazide (7.0 g, 42 mmol) in 500 mL of ethanol was warmed under a nitrogen atmosphere to dissolve all the solids and then the reaction stirred at room temperature for four days. The solid formed was collected by filtration and dried under reduced pressure to give 8.73 g of a white solid. Recrystallization of the solid from ethanol gave 7.99 g (57%) of the title compound as a white solid, mp 107-109° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH2:17]=O.[CH:19]1[CH:20]=[C:21]2[C:26]3=[C:27]([C:29]([NH:31][C:32](=[O:33])[C:25]3=[CH:24][CH:23]=[CH:22]2)=[O:30])[CH:28]=1>CN(C)C=O>[O:16]=[C:8]1[N:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:17][N:31]3[C:32](=[O:33])[C:25]4[CH:24]=[CH:23][CH:22]=[C:21]5[C:26]=4[C:27](=[CH:28][CH:19]=[CH:20]5)[C:29]3=[O:30])[CH2:6][CH2:5]2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9]1
Reactant: C=O
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Solvent: CN(C)C=O
Product: O=C1c2cccc3cccc(c23)C(=O)N1CN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
An equimolar mixture of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, aqueous formaldehyde and 1,8-naphthalimide is suspended in a small amount of dimethylformamide and the mixture is heated until dissolution is complete. The solution is allowed to stand at room temperature and the resulting precipitate is filtered off and dried to yield 2-[1-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]methyl]-1H-benz[de]isoquinoline-1,3(2H)-dione.
Reaction SMILES: C([N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH:29]C(=O)OC(C)(C)C)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Br[CH:38]([C:41]1[O:42][C:43](=[O:57])[C:44]2[C:49]([C:50]=1[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:39][CH3:40].[H-].[Na+]>CN(C=O)C>[N:24]1[C:25]([NH:29][CH:38]([C:41]2[O:42][C:43](=[O:57])[C:44]3[C:49]([C:50]=2[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:39][CH3:40])=[C:26]2[C:21]([NH:20][CH:28]=[N:27]2)=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(Br)c1oc(=O)c2ccccc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(Nc1ncnc2[nH]cnc12)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 2.4 %

Procedure:
The title compound was made in a similar way as that of the compound of example 21, from tert-butyl 9-trityl-9H-purin-6-ylcarbamate (167 mg, 0.350 mmol), 3-(1-bromopropyl)-4-phenyl-1H-isochromen-1-one (intermediate C20, 100 mg, 0.291 mmol) and 50% dispersion in mineral oil NaH (21 mg, 0.870 mmol) in DMF at 55° C. The crude was purified via reverse phase chromatography with a column stacking of two Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) and further purified by Preparative HPLC (method 1) to give the title compound (2.8 mg, 2.4%) as a colourless solid.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH:36]3[CH2:38][CH2:37]3)[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH:36]3[CH2:38][CH2:37]3)[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNC4CC4)c23)ccc1OCc1ccccn1
Reactant: O=C(O)CO
Product: O=C(CO)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C1CC1
Yield: 19 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(cyclopropylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 13, preparation of starting materials) to give the title compound in 19% yield; NMR spectrum (DMSO-d6) 0.73-0.80 (m, 4H), 2.73-2.80 (m, 1H), 3.90 (t, 2H), 4.24 (s, 3H), 4.44 (t, 2H), 5.31 (s, 2H), 7.20 (d, 1H), 7.25 (d, 1H), 7.35 (d, 1H), 7.36-7.40 (m, 1H), 7.57-7.62 (m, 2H), 7.71-7.76 (m, 1H), 7.86-7.92 (m, 1H), 8.01 (d, 1H), 8.46 (s, 1H), 8.61 (d, 1H), 9.80 (s, 1H); Mass spectrum MH+ 520.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCOCC1
Temperature: 140 °C

Procedure:
A mixture of 2-methoxy-4-nitrophenol Compound 42a1 (1.0 g, 5.4 mmol), potassium carbonate (1.5 g, 10.9 mmol) and 4-(2-chloroethyl)-morpholine hydrochloride Compound 42a2 (1.05 g, 5.64 mmol) in DMF (10 mL) was heated under microwave conditions to 140° C. for 30 minutes. The reaction mixture was filtered, diluted with EtOAc and subsequently washed with water, then brine. The organic layer was dried over sodium sulfate and concentrated to yield 4-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-morpholine Compound 42a3 (1.4 g). MS 283 (MH+).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]1[CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:30])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[C].[Pd]>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]1[CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:30]
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1CC1CCCN1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C1Nc2ccccc2C(c2ccccc2)N1CC1CCCN1
Yield: 75.4 %

Procedure:
To a solution of 15.98 g (40.2 mmol) of 3-(1-benzylpyrrolidin-2-yl)methyl-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 300 mL ethanol were added 13.61 g (216 mmol) of ammonium formate and 1.64 g of 10 % palladium-carbon, and the mixture was heated under reflux for 5 hours. After being cooled, the reaction mixture was filtered through cerite, and the filtrate was concentrated in vacuo. To the residue was added an aqueous saturated sodium hydrogencarbonate solution, and the mixture was extracted with chloroform. The organic layer separated was dried on potassium carbonate, and then concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 5:100:900 aqueous ammonia methanol:chloroform) to give 9.32 g (30.3 mmol) of the title compound as an about 1:1 mixture of the diastereomers.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.CS(C)=O.[OH:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:17][N:18]2[C:22](=[O:23])[C:21]3[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]2=[O:28])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
To a mixture of 659 mg of 1-(chloromethyl)-4-(methylsulfonyl)benzene and 10 ml of DMSO were added 525 mg of N-hydroxyphthalimide and 445 mg of potassium carbonate, followed by stirring at 50° C. for 2 hours. The reaction solution was cooled, water was then added thereto, and the precipitated crystal was collected by filtration to obtain 685 mg of 2-{[4-(methylsulfonyl)benzyl]oxy}-1H-isoindole-1,3(2H)-dione as a white solid.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].C(O[C:14](=[O:25])[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=1)C.[CH3:26][C:27]([C:29]1[CH:30]=[CH:31][C:32]([OH:36])=[CH:33][C:34]=1[OH:35])=[O:28]>O1CCCC1>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([C:14](=[O:25])[CH2:26][C:27]([C:29]2[CH:30]=[CH:31][C:32]([OH:36])=[CH:33][C:34]=2[OH:35])=[O:28])[CH:16]=[C:17]([O:23][CH3:24])[CH:18]=1
Reactant: CCOC(=O)c1cc(OC)cc(OC)c1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=O)CC(=O)c2ccc(O)cc2O)c1

Procedure:
A solution of 20% lithiumhexamethyldisilazane in tetrahydrofuran (144 mL, 172 mmol), 2,4-dihydroxy acetophenone, 14 (6.5 g, 43 mmol) in tetrahydrofuran (150 mL) and ethyl-3,5-dimethoxy benzoate, 6 (9 g, 43 mmol) in tetrahydrofuran (100 mL) were reacted to afford 20, 1-(3,5-dimethoxy-phenyl)-3-(2,4-dihydroxy-phenyl)-propane-1,3-dione (15 g), which was cyclized with Dowex-H+ (5 g) in 2-propanol (200 mL) in a similar way as described for 22 to afford 26. Yield 7.6 g (59%); mp 267-268° C.; MS (FAB) 299 (M++1); IR (KBr) 3405, 1602; 1H NMR (200 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.17 (d, J=2.0 Hz, 2H), 7.03 (d, J=1.9 Hz, 1H), 6.95 (s, 1H), 6.94 (dd, J=7.2 Hz, 2.0 Hz, 1H), 6.71 (s, 1H), 3.85 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:37])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:25][C@H:24]([CH2:26][O:27]C(=O)C4C=CC=CC=4)[C@@H:14]([O:15]C(=O)C4C=CC=CC=4)[C@@H:13]3[F:36])[C:6]=2[N:7]=1>N.CO.CO>[NH2:1][C:2]1[NH:3][C:4](=[O:37])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:25][C@H:24]([CH2:26][OH:27])[C@@H:14]([OH:15])[C@@H:13]3[F:36])[C:6]=2[N:7]=1
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c(=O)[nH]1
Agent: N
Solvent: CO
Product: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]1
Yield: 86.8 %

Procedure:
Treatment of 5-amino-3-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabinofuranosyl)thiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (0.40 g, 0.76 mmol) in NH3 /MeOH (saturated at 0° C., 35 mL) at room temperature for 24 h gavethe deblocked nucleoside. This was dissolved in MeOH, adsorbed on silica gel (10 g) and loaded on the top of a prepacked silica gel column. The column was eluted with CH2Cl2 :MeOH (90:10, v:v). The appropriate fractions were pooled and concentrated to afford 0.21 g (86.9%) of the title compound, mp 232°-234° C.; Ir (KBr): ν 3200-3450 (OH, NH), 1660 (C=O) and 1677 (C=O) cm-1. Uv, λ max (nm),(ε×10-3): pH 1, 302 (8.4), 242 (8.8), 222 (10.2); pH 7, 302 (8.6), 242 (9.1), 222 (10.3); pH 11, 220 (9.9), 242 (7.6), 294 (6.0); 1H nmr (DMSO-d6): δ 3.65 (t,2 H, C5'H2), 4.23 (m, 1 H, C4'H), 4.55 (tt, 1 H, C3'H), 4.72 (m, 1 H, C3'OH), 5.36 (tt, J2,HF=40.4 Hz, 1 H, C2'H),5.72 (m, 1 H, C5'OH), 6.30 (dd, J1',2' =2.12 Hz, 1 J1'H,F =12.52 Hz, 1 H, C1'H), 6.96 (br s, 2 H, NH2) and 11.25 (br s, 1H, NH); Anal. Calc'd for C10H11OF5S 0.25 CH3OH: C, 37.73; H, 3.71; N, 17.16: S, 9.82; F, 5.82. Found: C, 37.93; H, 3.86; N, 16.72; S, 9.53; F, 5.52.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].ClC[CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: N#CCCCCCCl
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCC#N)ccc(C(C)=O)c1O

Procedure:
A solution of 44.4 g. of 2,4-dihydroxy-3-propylacetophenone, 42.2 g. of 6-chlorocapronitrile, 33.2 g. of potassium carbonate and 4.0 g. of potassium iodide in one liter of methyl ethyl ketone was allowed to reflux for three days. The reaction mixture was filtered and the filtrate was evaporated in vacuo. Chromatography of the residue over silica gel (0-30% ethyl acetate gradient in hexane) gave 53.6 g. of the title product as an oil.