Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][N:10]2[C:22]3[CH:21]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH:19]=[C:18]([OH:33])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:34](=[O:36])[NH2:35])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[C:3]1([CH2:9][N:10]2[C:22]3[CH:21]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH:19]=[C:18]([O:33][CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:34](=[O:36])[NH2:35])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC(=O)c1cccc2c1c1c(O)cc(-c3ccc(C(F)(F)F)cc3)cc1n2Cc1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(-c2ccc(C(F)(F)F)cc2)cc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Reaction time: 0.12 h
Yield: 84 %

Procedure:
60% Sodium hydride in mineral oil (22 mg, 0.54 mM) was added to a solution of the 9-[(phenyl)methyl]-2-(4-trifluoromethylphenyl)-4-hydroxy-5-carbamoyl carbazole (0.20 g, 0.43 mM) in 15 mL DMF and 3 ml THF. After 7 minutes, methyl bromoacetate (56 μl, 0.59 mM) was added and the resultant mixture stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate and washed with H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layers were extracted with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 0.19 g (84%) of the {9-[(phenyl)methyl]-2-(4-trifluoromethylphenyl)-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester. 1H NMR (DMSO-d6) δ8.0 (d, J=8 Hz, 2H), 7.85 (d, J=8 Hz, 2H), 7.7 (s, 1H), 7.6 (d, J=8 Hz, 1H), 7.6 (bs, 1H), 7.4 (dd, J=8 and 8 Hz, 1H), 7.3-7.1 (m, 6H), 7.1 (d, J=8 Hz, 1H), 7.0 (s, 1H), 5.8 (s, 2H), 5.1 (s, 2H), 3.7 (s, 3H). MS (FD) m/e 516,533.
Reaction SMILES: [C:1]([CH:4]1[CH:9]([C:10](O)=[O:11])[CH2:8][CH2:7][CH:6]=[CH:5]1)(O)=[O:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.O>C1COCC1.C1C=CC=CC=1>[OH:2][CH2:1][C@H:4]1[C@@H:9]([CH2:10][OH:11])[CH2:8][CH:7]=[CH:6][CH2:5]1
Reactant: O=C(O)C1C=CCCC1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccccc1
Product: OC[C@@H]1CC=CC[C@@H]1CO
Temperature: 0 °C
Reaction time: 18 h
Yield: 102 %

Procedure:
A solution of the anhydride of 3,4-dicarboxycyclohex-1-ene (25.8 g) in THF (150 ml) is added with cooling to a stirred suspension of LiAlH4 (9 g) in THF (200 ml) under N2 at a rate such as to maintain the temperature at 0° C. After stirring for 18 hours at room temperature the mixture is gently refluxed for one hour and cooled in ice. The excess lithium aluminium hydride is decomposed by the careful addition of 1:1 THF-H2O mixture (100 ml). After dilution with chloroform (150 ml) the resulting mixture is filtered and the solid is washed with chloroform (3×25 ml). Concentration of the filtrate under reduced pressure yields an oily residue which is dissolved in benzene, dried over (MgSO4) and reconcentrated in vacuo to give the title compound as an oil (22 g, ca. 90%), νmax (film) 3350 cm-1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[C:33]1([CH2:39][S:40](Cl)(=[O:42])=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][S:40]([CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:42])=[O:41])[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: CS(=O)(=O)N(CCCNS(=O)(=O)Cc1ccccc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Compound 2 was coupled with phenyl-methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 610. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H), 8.0 (d, 1H) 7.5 (m, 3H) 7.3 (d, 2H), 7.2 (m, 4H), 6.7 (d, 4H), 4.4 (s, 2H), 4.2 (s, 2H), 3.6 (t, 2H), 3.2 (t, 2H), δ 2.9 (s, 3H), 2.7 (t, 2H), 2.7 (t, 2H), δ 1.6 (m, 2H).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].O.O1CCOCC1.[C:16]1(=[O:31])[C:29]2[C:20](=[CH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19](=[O:30])[CH:18]=[CH:17]1>O>[OH:30][C:19]1[C:20]2[C:29](=[CH:28][C:27]3[C:22]([CH:21]=2)=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:16]([OH:31])=[CH:17][CH:18]=1
Reactant: O=C1C=CC(=O)c2cc3ccccc3cc21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc(O)c2cc3ccccc3cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.4 %

Procedure:
A solution of sodium hydrosulfite (16.70 g, 42.0 mmol, 1 molar equivalent) in a water/dioxane (3/2) (250 mL) mixture is added under nitrogen to the 1,4-anthracenedione 1a (5.00 g, 24.0 mmol, 1 molar equivalent). The resulting mixture is stirred at room temperature for 3 h. Water is added and the resulting precipitate is filtered, washed with water and dried under vacuum to give the title compound as a yellow powder (3.10 g, 61%). 1H NMR (300.13 MHz, THF-d8) (ppm) 6.53 (s, 2H) 7.34-7.40 (m, 2H) 7.96-7.99 (m, 2H) 8.65 (s, 2H) 8.70 (s, 2H).
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:12][S:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:25]1[O:27][CH2:26]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(C)C>[CH2:13]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C@H:25]([OH:27])[CH2:26][N:9]1[C@H:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][S:11][CH2:10]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1CSCN1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 90 °C
Yield: 42.5 %

Procedure:
A solution of 3.2 g of N-tert.butyl-4(R)-thiazolidinecarboxamide and 5.0 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane in 130 ml of isopropanol was stirred under argon and heated at 90° C. under reflux for 3 days. The solution was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel using diethyl ethyl/n-hexane (2:1) for the elution. There were obtained 3.47 g of 3-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-4(R)-thiazolidinecarboxamide. Recrystallization from ethyl acetate gave analytically pure material of melting point 62°-65° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[CH:34]1([C:40](O)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.Cl.C(C(NCCCN(C)C)=N)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1.O>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([OH:20])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[CH:8]=3)[N:3]=[C:2]([NH:1][C:40]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:41])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(N)nc(-c3cccc(Cl)c3)c2c1
Reactant: O=C(O)C1CCCCC1
Agent: CCC(=N)NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(NC(=O)C3CCCCC3)nc(-c3cccc(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 4.9 %

Procedure:
A mixture of 2-amino-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (0.00021 mol), obtained in Example B19, cyclohexanecarboxylic acid (1.2 equiv, 0.000252 mol), N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine, monohydrochloride (1.5 equiv, 0.000315 mol), 1-hydroxy-1H-benzotriazole (1.5 equiv, 0.000315 mol) and triethylamine (1.5 equiv, 0.000315 mol) in THF (2 ml) was stirred at room temperature for 18 hours, then taken up in water. The organic layer was separated and the solvent was evaporated. The residue was purified by HPLC. The product fractions were collected and the solvent was evaporated, yielding 0.006 g (4.8%) of N-[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2-quinazolinyl]-cyclohexanecarboxamide, MS (ESI) m/z: 586 588 590.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][C:11](=[O:24])[CH2:12][O:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][N:27]([CH:29]=O)[CH3:28]>O>[CH2:1]([O:8][C:9](=[O:25])[C:10]([C:11](=[O:24])[CH2:12][O:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=[CH:26][N:27]([CH3:29])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(COC12CC3CC(CC(C3)C1)C2)CC(=O)OCc1ccccc1
Solvent: O
Product: CN(C)C=C(C(=O)COC12CC3CC(CC(C3)C1)C2)C(=O)OCc1ccccc1

Procedure:
A solution of 4-(adamantan-1-yloxy)-3-oxo-butyric acid benzyl ester (1.133 g, 3.3 mmol) and DMF dimethylacetal (0.56 mL, 3.96 mmol) in DMF (20 mL) was heated at 100° C. for 3 h. The mixture was diluted with H2O (80 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (2×30 mL), and dried (MgSO4). Filtration and evaporation of the solvent afforded the product, (0.647 g, 49%).
Reaction SMILES: I[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:9]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[C:22]([F:27])[C:23]([I:26])=[C:24]([F:25])[C:19]=3[NH:18][C:17]2=[S:28])=[CH:11][CH:10]=1>C1COCC1>[C:9]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[C:22]([F:27])[C:23]([I:26])=[C:24]([F:25])[C:19]=3[N:18]=[C:17]2[S:28][CH3:2])=[CH:11][CH:10]=1
Reactant: Fc1cc2c([nH]c(=S)n2Cc2ccc(-c3ccccc3)cc2)c(F)c1I
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CSc1nc2c(F)c(I)c(F)cc2n1Cc1ccc(-c2ccccc2)cc1

Procedure:
Iodomethane (2 Min methyl-tert-butyl ether, 22.87 mL, 45.7 mmol) was added to a solution of cesium carbonate (14.9 g, 45.7 mmol) and 1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-1,3-dihydro-2H-benzimidazole-2-thione (10.94 g, 22.87 mmol) in THF (100 mL). After stirring the reaction at rt overnight, the volatiles were removed. Chromatography of the resulting residue over silica eluting with 15-60% EtOAc/hexanes afforded the desired product as a beige solid.
Reaction SMILES: Br[C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O.[NH2:19][NH2:20]>>[Br:10][C:11]1[CH:12]=[C:13]([C:14]2[C:2]3[C:3](=[N:4][C:5]([Cl:8])=[N:6][CH:7]=3)[NH:20][N:19]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NN
Reactant: O=Cc1cccc(Br)c1
Product: Clc1ncc2c(-c3cccc(Br)c3)n[nH]c2n1

Procedure:
Alternatively, for compounds of formula Ib where X and Y are CH, in accordance to Scheme 3 below, 5-bromo-2,4-dichloro-pyrimidine (1) is reacted with 3-bromo-benzaldehyde (4) by a Grignard reaction and the corresponding coupled alcohol is oxidized to the ketone. The ketone is reacted with hydrazine to give 3-(3-bromo-phenyl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidine. The remaining chloro group can then be replaced by reacting with the appropriate amine and the bromide can be displacement with the required amine under Buckwald conditions to give compounds Ib of this invention.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[CH:39]=[CH:38][S:37][CH:36]=2)=[O:34])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[C:5]2[CH:23]=[CH:24][C:2]([C:27]3[CH:28]=[C:29]([NH:32][C:33]([C:35]4[CH:39]=[CH:38][S:37][CH:36]=4)=[O:34])[CH:30]=[CH:31][C:26]=3[CH3:25])=[N:3][CH:4]=2)[CH2:17][CH2:18]1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS: retention time 2.58 min, MH+ 526. NMR: δH [2H6]-DMSO 11.64,(1H, b), 10.14,(1H, s), 9.23,(1H, s), 8.38,(2H, m), 8.31,(1H, d), 7.91,(1H, s), 7.79-7.75,(2H, m), 7.65,(2H, in), 7.38-7.29,(3H, m), 7.11,(1H, t), 3.77,(2H, s), 2.67-2.24,(11H, m), 2.16,(3H, m).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1>C(OOC(C)(C)C)(=O)C(C)(C)C.ClC1C=CC=CC=1>[C:12]1([C:3]2=[CH:2][C:1]([O:6][C:4]2=[O:5])=[O:7])[CH2:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1=CCC=C1
Reactant: O=C1C=CC(=O)O1
Agent: CC(C)(C)OOC(=O)C(C)(C)C
Solvent: Clc1ccccc1
Product: O=C1C=C(C2=CC=CC2)C(=O)O1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
The copolymerization of 1.2 g (12 mmoles) of maleic anhydride with 0.8 g. (12 mmoles) of cyclopentadiene using 0.3 ml. (1 mmole) of t-butyl peroxypivalate as catalyst at 80° C. was carried out in the presence of 1.8 ml. of chlorobenzene, using the procedure described in Example VI. The catalyst addition was carried out over a period of 10 min. and the reaction mixture was then maintained at 80° C. for an additional 50 min. The 1:2 cyclopentadiene-maleic anhydride copolymer was obtained in a yield of 0.64 g. (40%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[N:3]=1
Reactant: C1CCNCC1
Reactant: Cc1cccc(Cl)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(CN2CCCCC2)n1
Yield: 41 %

Procedure:
To 2-chloro-6-methylpyridine (50.0 g, 0.392 mole) in 393 mL of carbon tetrachloride was added N-bromosuccinimide (87.2 g, 0.49 mole) and 1.0 g of benzoyl peroxide. The mixture was stirred at reflux for 22 hours, cooled to 10° and filtered. The chilled filtrate then was treated slowly with piperidine (83.5 g, 0.98 mole) and allowed to stir at ambient temperature for 18 hours. After removal of the piperidine hydrobromide by filtration, the filtrate was concentrated to about half volume and extracted with 6N HCl (65 mL) and 3N HCl (40 mL). The acid extracts were made basic with 40% sodium hydroxide and the product was extracted into methylene chloride. The solvent was evaporated and the residue distilled to yield 41% of the title compound as a colorless oil, b.p. 101°-103°/0.45 mm Hg.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:3]1.[C:17](OC=C)(=[O:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(O)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CC(CC(C)C)=O>[C:17]([O:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:3]1)(=[O:19])[CH3:18]
Reactant: COc1cccc(CC2=CC(O)CC2=O)c1
Reactant: C=COC(C)=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CC(=O)CC(C)C
Product: COc1cccc(CC2=C[C@H](OC(C)=O)CC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
4-Hydroxy-2-(3-methoxybenzyl)cyclopent-2-enone (9 g, 41.26 mmol) was dissolved in isobutyl methyl ketone (90 mL), and vinyl acetate (8.4 g, 97.57 mmol) and Lipase derived from Pseudomonas cepacia (0.9 g) were added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove the Lipase and the filtrate was evaporated. The resulting residue was dissolved in PhCH3 (150 ml), and triphenylphosphine (6.5 g; 24.78 mmol) and AcOH (1.61 g, 26.81 mmol) were added to the solution. Then diisopropylazodicarboxylate (5 g, 24.72 mmol) was added to the mixture at 5° C. After the reaction was completed, the reaction mixture was filtered to remove the precipitate and the filtrate was evaporated. The residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give the (R)-3-(3-methoxybenzyl)-4-oxocyclopent-2-enyl acetate as yellow oil: 10 g (yield: 93%, 95% ee by HPLC using a chiral column)
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][CH:16]([CH3:19])[CH2:17]O>O1CCCC1>[CH3:19][C:16]1[NH:15][C:11]2[CH2:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][C:9](=[O:14])[C:10]=2[CH:17]=1
Reactant: CC(N)CO
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Solvent: C1CCOC1
Product: Cc1cc2c([nH]1)CC(c1ccccc1)CC2=O
Temperature: 150 °C
Reaction time: 3.5 h
Yield: 66.8 %

Procedure:
A mixture of 5-phenylcyclohexane-1,3-dione (4.0 g), 2-aminopropanol (2.1 g), molecular sieves 4A (24 g) and tetrahydrofuran (60 ml) was refluxed for 14 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (100 ml). To the solution were added 2-bromomesitylene (4.2. g), tetrakistriphenylphosphine palladium (0.6 g) and potassium carbonate (5.9 g), and the mixture was stirred at 150° C. for 3.5 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc), and the resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 2-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (3.2 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][C:19]([CH3:21])=[CH2:20]>>[C:1]([O:5][C:6](=[O:16])[CH2:7][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:20][C:19]([CH3:21])=[CH2:18])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CNC(=O)OC(C)(C)C
Reactant: C=C(C)CBr
Product: C=C(C)CN(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
N-(tert-Butoxycarbonyl)glycine tert-butyl ester was reacted with 3-bromo-2-methylpropene according to Method B8b, Step 1 to give N-(tert-butoxycarbonyl)-N-(2-methylprop-2-enyl)glycine tert-butyl ester. The ester was reduced according to Method B8b, Step 2 to give N-(tert-butoxycarbonyl)-N-(2-hydroxyethyl)-1-amino-2-methylprop-2-ene. The alcohol was treated with p-toluenesulfonyl chloride according to Method B8b, Step 3 to give N-(tert-butoxycarbonyl)-N-(2-tosyloxyethyl)-1-amino-2-methylprop-2-ene. The carbamate was deprotected according to Method B8b, Step 4 to give N-(2-tosyloxyethyl)-2-methylprop-2-en-1-ammonium trifluoroacetate. The tosylate was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C5a to afford 2-(2-methyl-4-nitrophenylimino)-3-(2methylprop-2-enyl)-1,3-oxazolidine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Br:17]Br>C(O)C.O1CCOCC1>[Br:17][CH2:2][C:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CCOC(=O)/C=C/c1cccc(C(C)=O)c1
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)/C=C/c1cccc(C(=O)CBr)c1
Reaction time: 1 h

Procedure:
10.9 g of ethyl (E)-3-(3-acetylphenyl)acrylate was dissolved in 50 ml of ethanol and 5 ml of dioxane. To the solution was dropwise added 8.8 g of bromine in 2 hours at 15° to 20° C. The mixture was stirred for 1 hour at the same temperature. The solvent was removed by distillation under reduced pressure to obtain ethyl (E)-3-[3-(2-bromoacetyl)phenyl]acrylate.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.O.C>CO>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2csc(C#N)n2)cc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1nc(-c2ccc(O)cc2)cs1
Temperature: 225 °C
Yield: 66 %

Procedure:
A mixture of 4-(4-methoxyphenyl)-thiazole-2-carbonitrile (14.9 g) and pyridine hydrochloride (44.7 g) was heated at 225° C. for 1 h, then cooled and added to water (300 ml). The suspension was filtered and dried under vacuum at 50° C., to give a solid which was dissolved in methanol, treated with charcoal, filtered and recrystallised from methanol-water to give 4-(4-hydroxyphenyl)-thiazole-2-carbonitrile (9.2 g); m.p. 186°-197 ° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].[N:19]([CH2:22][CH2:23][CH2:24][N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][C:28]([NH2:35])=[N:29][C:30]=2Cl)=[N+:20]=[N-:21].FC(F)(F)C(O)=O>CC(N(C)C)=O.O>[NH2:35][C:28]1[N:27]=[C:26]2[C:31]([N:32]=[CH:33][N:25]2[CH2:24][CH2:23][CH2:22][N:19]=[N+:20]=[N-:21])=[C:30]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[N:29]=1
Reactant: [N-]=[N+]=NCCCn1cnc2c(Cl)nc(N)nc21
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NCCCn1cnc2c(OCc3ccc(CNC(=O)C(F)(F)F)cc3)nc(N)nc21
Temperature: 90 °C

Procedure:
2,2,2-Trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide (138 mg, 0.59 mmol) is dissolved in 3 mL dry dimethylacetamide under argon atmosphere, and (31 mg, 1.31 mmol) NaH is added. N9-(3-Azidopropyl)-2-amino-6-chloropurine (22, 100 mg, 0.39 mmol) is added and the solution heated to 90° C. for 16 h. After cooling to room temperature, the mixture is poured into 80 mL of water and the pH is adjusted to 6 with trifluoroacetic acid. The aqueous phase is extracted with CH2Cl2 and ethyl acetate. The organic phases are washed with water and brine, dried over MgSO4 and the solvent is evaporated. The crude product is dissolved in methanol, adsorbed on SiO2 (150 mg) and purified by flash column chromatography with dichloromethane:methanol (95:5). Yield: 151 mg (0.0336 mmol, 85%). 1H-NMR (400 MHz, DMSO-d6): δ=10.00 (t, J=5.8, 1H, CF3CONH), 7.90 (s, 1H, H-8), 7.49, (d, J=8.1, 2H, ArH), 7.28 (d, J=8.1, 2H, ArH), 6.47 (s br, 2H, NH2), 5.46 (s, 2H, OCH2), 4.38 (d, J=5.8, 2H, CH2NH), 4.06 (t, J=6.5, 2H, CH2), 3.36 (t, J=6.5, 2H, CH2), 2.00 (m, 2H, CH2) ppm. MS (ESI) m/z 450.0 [M+H]+.
Reaction SMILES: COCCS(F)(F)([F:11])(CCOC)N.[C:14]([O:30][C@@:31]12[N:38]([CH3:39])[C@@H:35]([CH2:36][CH2:37]1)[CH2:34][CH:33]=[CH:32]2)(=[O:29])[C:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)O>C(Cl)(Cl)Cl>[C@@:31]12([OH:30])[N:38]([CH3:39])[C@@H:35]([CH2:36][CH2:37]1)[CH2:34][CH:33]=[CH:32]2.[F:11][C:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([O-:30])=[O:29]
Reactant: COCCS(N)(F)(F)(F)CCOC
Reactant: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1ccccc1)c1ccccc1)CC2
Solvent: ClC(Cl)Cl
Product: CN1[C@@H]2CC=C[C@@]1(O)CC2
Product: O=C([O-])C(F)(c1ccccc1)c1ccccc1

Procedure:
15.86 ml (0.086 mol) of bis-(2-methoxyethyl)-aminosulphur trifluoride are reacted with 25 g (0.072 mol) of 5f analogously to Example 4, step 4.3 in 480 ml of chloroform. The product is recrystallised from acetone in the form of its hydrochloride. Yield: 18.6 g of white crystals (=67% of theory);