Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][NH:4][C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(NCCO)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1NCCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(OCc3ccccc3)c21
Reaction time: 0.25 h
Yield: 484.1 %

Procedure:
To a solution mixture of 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-amide (347) (140 mg, 0.28 mmol) and diisopropyl azodicarboxylate (0.28 mL, 1.41 mmol) in dichloromethane (70 mL) was added triphenyl phosphine (443 mg, 1.69 mmol) at room temperature and the reaction mixture was stirred for 15 min at the same temperature. The yellow color disappeared (silica TLC, ethyl acetate 100%; Rf=0.2). The dichloromethane was removed in vacuum to get 9-benzyloxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (348) (650 mg, crude) which was used directly in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:8][CH:7]=1)=[O:4].[K+].[N+:21]([O-])([OH:23])=[O:22]>C(OCC)C>[CH3:1][O:2][C:3]([CH2:5][C:6]1[C:15]2[C:10](=[C:11]([N+:21]([O-:23])=[O:22])[CH:12]=[CH:13][CH:14]=2)[C:9]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:8][CH:7]=1)=[O:4]
Reactant: COC(=O)Cc1ccc(S(=O)(=O)[O-])c2ccccc12
Reactant: O=[N+]([O-])O
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)Cc1ccc(S(=O)(=O)O)c2c([N+](=O)[O-])cccc12
Temperature: -15 °C
Reaction time: 2 h

Procedure:
Potassium 1-(methoxycarbonylmethyl)-4-naphthalene sulfonate (10 g, 31.4 mmol) was added portionwise over 30 minutes to 90% nitric acid, which was cooled in a methanol/ice bath to approximately -15° C. After 2 hours, the bath temperature had reached -10° C. and diethyl ether (200 mL) was added to the mixture. The precipitated solid was filtered, washed with ether (100 mL) and isopropanol (20 mL), and dried under a stream of nitrogen to give the title compound as an approximately 70:30 mixture of the 5- and 8-nitro isomers (approximately 12 g).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1
Reactant: BrCCc1ccccc1
Reactant: CNC1CCNC1
Product: CNC1CCN(CCc2ccccc2)C1

Procedure:
3-Methylaminopyrrolidine and 2-bromoethylbenzene are reacted under the same conditions as in Starting Material Synthetic Example 4 to give 3 -methylamino-1-(2-phenylethyl)pyrrolidine.
Reaction SMILES: C(OC([N:8]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:11]2[CH2:18][CH2:19][CH2:20][C:10]2([F:21])[C:9]1=[O:22])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O.C(OCC)(=O)C>[F:21][C:10]12[CH2:20][CH2:19][CH2:18][CH:11]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[NH:8][C:9]2=[O:22]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(F)CCCC2c2ccccc21
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2ccccc2C2CCCC12F
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A solution of 350 mg (1.1 mmol) of 5-tert-butoxycarbonyl-3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 5 mL of dichloromethane is mixed with 5 ml of trifluoroacetic acid at room temperature. After 1 hour, the batch is diluted with water (100 ml) and ethyl acetate (100 ml). The organic phase is separated, washed with water (50 ml), saturated NaHCO3, (2×50 ml) and saturated NaCl (50 ml), dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography of the residue on silica gel with hexane-ethyl acetate yields 160 mg of product.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([OH:13])[CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].[C:17](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[OH:1][C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:11])[CH3:12])=[C:6]([O:13][CH3:17])[CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(O)c(CC=C(C)C)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C(C)=O)c(O)c1CC=C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
Then, 19.00 g of 2',4'-dihydroxy-3'-(3-methyl-2-butenyl)acetophenone was dissolved in 160 ml of acetone, and 14.29 g of anhydrous potassium carbonate and 6.2 ml of methyl iodide were added to the solution and the mixture was stirred at room temperature in a nitrogen current overnight. After the reaction, the solvent was removed by distillation and the obtained residue was extracted with ether, the extract was washed with water, dried with anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate by distillation to obtain 20.02 g (yield=99.1%) of 2'-hydroxy-4'-methoxy-3'-(3-methyl-2-butenyl)acetophenone in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[C:22]([F:25])([F:24])[F:23])[S:14][CH:15]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH2:30]([NH2:32])[CH3:31]>>[CH2:30]([NH:32][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[C:22]([F:24])([F:25])[F:23])[S:14][CH:15]=2)[CH:9]=[CH:10][C:2]=1[F:1])[CH3:31]
Reactant: CCN
Reactant: O=C(O)c1cc(-c2csc(-c3cnccc3C(F)(F)F)n2)ccc1F
Solvent: O=S(Cl)Cl
Product: CCNC(=O)c1cc(-c2csc(-c3cnccc3C(F)(F)F)n2)ccc1F

Procedure:
By the reaction in the same manner as in Example 60 using 2-fluoro-5-{2-[4-(trifluoromethyl)pyridin-3-yl]-1,3-thiazol-4-yl}benzoic acid (202 mg), thionyl chloride (0.06 ml) and aqueous ethylamine solution (70%, 5 ml), the title compound (139 mg) was obtained as colorless powder crystals.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1>CC(N(C)C)=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([O:36][C:33]3[CH:34]=[CH:35][C:30]([Br:29])=[CH:31][C:32]=3[F:37])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1c(Oc2ccc(Br)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 160 °C
Yield: 34.5 %

Procedure:
A mixture of 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (2.19 g, 6.7 mmol), potassium carbonate (1.84 g, 13.3 mmol), and 4-bromo-2-fluorophenol (1.65 g, 8.65 mmol) in 32 ml DMA was heated at 160° C. for 5 hours. The mixture was extracted with AcOEt and brine. Organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by HPLC to give 4-[6-(4-bromo-2-fluoro-phenoxy)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester as an oil (1.12 g, 35%). Exact mass calculated for C20H23BrFN3O5 483.08. found 484.4 (MH+).
Reaction SMILES: [N:1]1([C:6]2[C:7]3[NH:14][CH:13]=[C:12]([C:15]([O:17]CC)=[O:16])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.O[Li].O.CO>C1COCC1.O>[N:1]1([C:6]2[C:7]3[NH:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1c[nH]c2c(-n3cccn3)ncnc12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1c[nH]c2c(-n3cccn3)ncnc12
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(1H-pyrazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate 49 (2.0 g, 7.8 mmol) in THF (45 mL) was added a solution of LiOH.H2O (1.3 g, 31 mmol) in H2O (30 mL) and the reaction was stirred at 100° C. for 16 h. Additional LiOH.H2O (2.0 g, 48 mmol) was added, heating continued for 2 h, MeOH was added (10 mL) and heating continued at 100° C. for 1d. The reaction mixture was cooled, filtered, concentrated to ˜20% volume and neutralized with ice and conc HCl. The white precipitate that formed was collected by filtration and washed with brine, H2O, EtOAc, and Et2O to yield 50 (quantitative), which was used without further purification. 1H NMR: (500 MHz, DMSO-d6) δ 12.07 (br s, 1H), 8.89 (br s, 1H), 8.75 (s, 1H), 8.14 (s, 1H), 8.09 (br s, 1H), 6.76-6.73 (m, 1H);
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Br:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[Br:14].C([O-])([O-])=[O:16].[Ca+2]>O1CCOCC1.O>[Br:14][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:13])[C:3]=1[CH2:2][OH:16])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)c(CBr)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(Br)c(CO)c(Br)c1
Temperature: 100 °C

Procedure:
To a stirred solution of methyl 3,5-dibromo-4-(bromomethyl)benzoate (INTERMEDIATE 24) (12.53 g, 32.4 mmol, 1 eq) in dioxane (100 mL) and water (100 mL) was added CaCO3 (8.1 g, 81 mmol, 2.5 eq). The mixture was warned to and stirred at 100° C. until reaction was complete by HPLC analysis. The mixture was cooled and the solvent removed under reduced pressure. The residue was diluted with water and extracted 3× with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated giving methyl 3,5-dibromo-4-(hydroxymethyl)benzoate. The material was taken immediately to the next step.
Reaction SMILES: C([O:5][C:6](=[O:16])[CH2:7][CH2:8][CH2:9][C@@H:10]([O:12][N+:13]([O-:15])=[O:14])[CH3:11])(C)(C)C>C(Cl)Cl>[N+:13]([O:12][C@@H:10]([CH3:11])[CH2:9][CH2:8][CH2:7][C:6]([OH:16])=[O:5])([O-:15])=[O:14]
Reactant: C[C@@H](CCCC(=O)OC(C)(C)C)O[N+](=O)[O-]
Solvent: ClCCl
Product: C[C@@H](CCCC(=O)O)O[N+](=O)[O-]

Procedure:
(S)-tert-butyl-5-(nitrooxy)hexanoate (590 mg, 2.53 mmol), was dissolved in CH2Cl2 (20 mL). HClgas was bubbled into the solution until the disappearance of the starting material. The solution was reduced to a small volume and diluted in CH2Cl2 few times to remove residual acidity, then used without further purification.
Reaction SMILES: [S:1]([O:11][CH:12](OS(C1C=CC(C)=CC=1)(=O)=O)/[CH:13]=[CH:14]/[CH3:15])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CC1C=CC([C@@H]2C(C(O[11CH3])=O)C3N(C/C=C/C[F:50])[C@H](CC3)C2)=CC=1.NCCC1C=CC(O)=C(O)C=1>>[C:7]1([CH3:8])[CH:9]=[CH:10][C:4]([S:1]([O:11][CH2:12]/[CH:13]=[CH:14]/[CH2:15][F:50])(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Cc1ccc([C@H]2C[C@H]3CCC(C2C(=O)O[11CH3])N3C/C=C/CF)cc1
Reactant: C/C=C/C(OS(=O)(=O)c1ccc(C)cc1)OS(=O)(=O)c1ccc(C)cc1
Agent: NCCc1ccc(O)c(O)c1
Product: Cc1ccc(S(=O)(=O)OC/C=C/CF)cc1
Yield: 28 %

Procedure:
This compound was prepared, starting from (E)-but-2-enediol ditosylate (0.50 g, 1.26 mmol), according to the procedure described by Dollé, F.; Emond, P.; Mavel, S.; Demphel, S.; Hinnen, F.; Mincheva, Z.; Saba, W.; Valette, H.; Chalon, S.; Halldin, C.; Helfenbein, J.; Legaillard, J.; Madelmont, J. C.; Deloye, J. B.; Bottlaender, M.; Guilloteau, D. Synthesis, radiosynthesis and in vivo preliminary evaluation of [11C]LBT-999, a selective radioligand for the visualisation of the dopamine transporter with PET Bioorg. Med. Chem. 2006, 14, 1115-1125. Reaction time under reflux: 1 h; the purification was performed using column chromatography (SiO2, CH2Cl2/pentane, 8/2, v/v) to give compound 55 (87 mg, 0.36 mmol) as a colourless oil. Yield 28%; Rf (SiO2, CH2Cl2/pentane, 8/2, v/v) 0.42; IR (CCl4) ν 1179, 1190, 1375, 1599 cm−1; 1H NMR (200 MHz, CDCl3) δ 2.45 (s, 3H), 4.57 (m, 2H), 4.82 (dd, 2H, 2JH-F=46.7 Hz, J=4.7 Hz), 5.85 (m, 2H), 7.36 (d, 2H, J=8.2 Hz), 7.79 (d, 2H, J=8.2 Hz).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(SCCOC3C=C(C#N)C=CN=3)=N2)C=CC=CC=1.[C:37]1([C:43]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[N:44]2[CH:48]=[N:47][C:46]([O:49][CH2:50][CH2:51][O:52][C:53]3[CH:54]=[C:55]([CH:58]=[CH:59][CH:60]=3)[C:56]#[N:57])=[N:45]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:67]1([C:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[N:44]2[CH:48]=[N:47][C:46]([O:49][CH2:50][CH2:51][O:52][C:53]3[CH:54]=[C:55]([CH2:56][NH2:57])[CH:58]=[CH:59][CH:60]=3)=[N:45]2)[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: N#Cc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: N#Cc1ccnc(OCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1

Procedure:
By a method similar to that in Reference Example 20 and using, instead of 2-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]thio}ethyl)oxy]pyridine-4-carbonitrile, 3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]benzonitrile obtained in Reference Example 31, the title compound was obtained as a colorless oil (504 mg, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].Br[CH:13]([CH2:15][CH3:16])[CH3:14]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:13]([CH2:15][CH3:16])[CH3:14])[N:6]=[C:5]2[I:11]
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: CCC(C)Br
Product: CCC(C)n1nc(I)c2cc(F)ccc21
Yield: 41 %

Procedure:
The title compound was prepared in 41% yield from 5-fluoro-3-iodo-indazole and 2-bromobutane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.79 (3H, t, J=7.2 Hz), 1.57 (3H, d, J=6.9 Hz), 1.88-1.95 (1H, m), 2.06-2.13 (1H, m), 4.48-4.55 (1H, m), 7.13 (1H, dd, J=2.1, 8.4 Hz), 7.20 (1H, dd, J=2.4, 9.0 Hz), 7.36 (1H, dd, J=3.9, 9.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8](=[O:12])[CH2:9][N:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[Cl:26][C:27]1[CH:52]=[CH:51][C:30]([C:31]([O:33][C@@H:34]2[C@@H:38]([CH2:39][O:40][C:41](=[O:49])[C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=3)[O:37][C@H:36](Cl)[CH2:35]2)=[O:32])=[CH:29][CH:28]=1>C[Si](C)(C)N[Si](C)(C)C.C(Cl)Cl.Cl([O-])(=O)(=O)=O.[Ag+]>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[N:7]([C@@H:36]3[O:37][C@H:38]([CH2:39][O:40][C:41](=[O:49])[C:42]4[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=4)[C@@H:34]([O:33][C:31](=[O:32])[C:30]4[CH:51]=[CH:52][C:27]([Cl:26])=[CH:28][CH:29]=4)[CH2:35]3)[C:6]=2[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: O=C(OC[C@H]1O[C@H](Cl)C[C@@H]1OC(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: Nc1nc(-c2ccccc2)nc2c1=NCC(=O)N=2
Agent: [Ag+]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: Nc1nc(-c2ccccc2)nc2c1ncc(=O)n2[C@H]1C[C@H](OC(=O)c2ccc(Cl)cc2)[C@@H](COC(=O)c2ccc(Cl)cc2)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1.0 g (4.2 mmol) of 4-amino-2-phenyl-pteridine-7-one (3) and a few crystals of ammonium sulfate was heated in 100 mL of hexamethyldisilazane (HMDS) under reflux for 4 hours. After cooling the excess HMDS was distilled off in vacuum and the residue dissolved in 100 mL of dry toluene. To the mixture was added 2.17 g (4.6 mmol) of 2-deoxy-3,5-di-O-(4-chlorobenzoyl)-α-D-ribofuranosyl chloride (made as in Example 3, step (a) for the toluyl derivative) and 0.476 g (2.3 mmol) of silver perchlorate. The solution was then stirred under anhydrous conditions for 24 hours at room temperature and then diluted with 200 mL of CH2Cl2. The resulting AgCl precipitate was filtered off through silica and then the filtrate was treated with 100 mL of a saturated aqueous solution of sodium bicarbonate followed by 100 mL of a saturated aqueous solution of NaCl. The organic layer was dried over Na2SO4, filtered and then the filtrate evaporated.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]([C@H:13]2[C@H:18]([C:19]([CH3:21])=[CH2:20])[CH2:17][CH2:16][C:15]([CH3:22])=[CH:14]2)=[C:10]([OH:12])[CH:11]=1>ClCCl>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[C:9]2[C@@H:13]3[CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][C@H:18]3[C:19]([CH3:21])([CH3:20])[O:23][C:8]=2[CH:7]=1
Reactant: C=C(C)[C@@H]1CCC(C)=C[C@H]1c1c(O)cc(CCCCC)cc1O
Solvent: ClCCl
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21

Procedure:
To a solution of cannabidiol (500 mg) in dichloromethane (8.75 mL) at 20° C., was added a solution of an organoaluminum-based Lewis acid catalyst in dichloromethane (1.0 mL) over five minutes and the reaction mixtures stirred under nitrogen and monitored by HPLC. Table 1 below shows the relative HPLC quantitation of the different product compounds in area percent at the time specified, using different organoaluminum-based Lewis acid catalysts.
Reaction SMILES: [H-].[Na+].C(=O)=O.[N:6]1([CH2:11][CH:12]([OH:25])[CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:10]=[CH:9][N:8]=[CH:7]1.[Cl:26][C:27]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:28]=1[CH2:29]Cl>C(COC)OC.O.CC(C)=O>[Cl:26][C:27]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:28]=1[CH2:29][O:25][CH:12]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)[CH2:11][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)c1ccc(SCC(O)Cn2ccnc2)cc1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)c1ccc(SCC(Cn2ccnc2)OCc2ccc(Cl)cc2Cl)cc1
Temperature: -20 °C

Procedure:
A dry 250-ml round bottom flask equipped with stir bar, addition funnel and N2 inlet was charged with dry dimethoxyethane (25 ml) and sodium hydride [60% (0.79 g, 0.0265 moles)]. The resulting slurry was cooled to -35° C. (with an external dry ice and acetone bath); then 1-(1-imidazolyl)-3-(4-tert-butylphenylthio)-propan-2-ol, 5.0 g (0.0172 moles), in 10 ml dry dimethoxyethane was added dropwise. After the addition was complete, the reaction mixture was allowed to warm to about -20° to -10° C. and was stirred at that temperature until no more H2 evolution was apparent. The reaction mixture was then cooled to -20° C. and 3.7 g (0.0189 mole) 2,4-dichlorobenzyl chloride were added very slowly. After the addition was complete, the reaction mixture was allowed to come to room temperature and was allowed to stir overnight. The reaction mixture was poured into water and ice and then extracted with ethyl acetate (twice). The ethyl acetate extracts were combined and washed with water until neutral. The ethyl acetate phase was dried, filtered, and then concentrated to give an oil which was chromatographed to give 2.0 g of the above-identified product.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[C:29]4[O:28][CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].C(N(CC)C(C)C)(C)C.Br[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(#N)C>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[C:29]4[O:28][CH2:27][CH2:26][N:25]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1C#N
Reactant: CCOC(=O)CCBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Temperature: 80 °C
Yield: 38.5 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 32) (90 mg, 0.218 mmol) in acetonitrile (10 ml) was added N,N-diisopropylethylamine (0.076 ml, 0.436 mmol) followed by ethyl 3-bromopropanoate (0.056 ml, 0.436 mmol). The reaction mixture was heated at 80° C. overnight. A further 1 equivalent of N,N-diisopropylethylamine and ethyl 3-bromopropanoate were added and heating continued overnight. The reaction mixture was cooled and evaporated. Purification of the residue by column chromatography on silica, eluting with 60-70% ethyl acetate in cyclohexane to give the title compound as a brown oil (40 mg).
Reaction SMILES: [H-].[Na+].[CH:3]12[CH:8]([CH2:9][OH:10])[CH:7]1[CH2:6][O:5][CH2:4]2.[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26](F)=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:15]=[CH:16][C:17]=1[F:18]>CN(C=O)C>[CH:3]12[CH:8]([CH2:9][O:10][C:22]3[N:21]=[C:20]([NH:19][C:14]4[CH:15]=[CH:16][C:17]([F:18])=[C:12]([Cl:11])[CH:13]=4)[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=4)[N:23]=3)[CH:7]1[CH2:6][O:5][CH2:4]2
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Reactant: OCC1C2COCC12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2nc(OCC3C4COCC43)nc(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
NaH (60% dispersion in mineral oil, 480 mg, 12.0 mmol) was added in portions to a stirring solution of (3-oxa-bicyclo[3.1.0]hexan-6-yl)methanol (570 mg, 5.0 mmol; prepared according to procedures described in WO2012/021591A1) in DMF (40 mL) at room temperature under N2 (g) atmosphere. After 20 min, the mixture was cooled to 0° C., followed by addition N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine 1a (1.54 g, 4.6 mmol, prepared according to Smaill, J. B., et al., Journal of Medicinal Chemistry, 2000, 43, 1380-1397). The reaction was quenched after stirring 30 min at 0° C. by a slow addition of saturated NH4Cl, followed by extraction with EtOAc (100 mL). The organic layer was washed with H2O (2×50 mL), brine (50 mL), dried over MgSO4, and concentrated to a yellow residue 2b, product was used directly for the next step. MS m/z (ESI+), 431 [M+1].
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])=[CH:6][CH:7]=1.[CH3:23][O-:24].[Na+].O>CO>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[N:10]=[C:9]([CH3:22])[N:8]([C:5]3[N:4]=[N:3][C:2]([O:24][CH3:23])=[CH:7][CH:6]=3)[CH:12]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: C[O-]
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccc(Cl)nn1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)nn1
Temperature: 25 °C

Procedure:
3-Chloro-6-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-pyridazine (100 mg, 0.30 mmol) was dissolved in 2 mL methanol and 1.5 mL sodium methanolate solution were added. The reaction mixture was refluxed for 3 h. After cooling to room temperature the reaction mixture was treated with 30 mL water and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated and the desired product was obtained as a white solid (53 mg, 53%), MS: m/e=325.3 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[O:7][C:8](=[O:15])[CH:9]3[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH:5]23.[Cl:16][CH2:17][C:18](Cl)=[O:19].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:16][CH2:17][C:18]([O:1][CH:2]1[CH:6]2[O:7][C:8](=[O:15])[CH:9]3[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH:5]23)=[O:19]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)C1C2CC3C(OC(=O)C31)C2O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
In 180 ml of tetrahydrofuran were dissolved 25.0 g of methyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta-[b]furan-7-carboxylate and 16.0 g of 2-chloroacetic acid chloride. To the solution below 20° C., 10.7 g of pyridine was added dropwise. The solution was stirred at room temperature for 1 hour and combined with 40 g of a 5% aqueous solution of sodium hydrogen carbonate, followed by ordinary post-treatment. Recrystallization from isopropyl ether gave 31.5 g of the target compound (yield 93%).