Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][P:6]([C:13]([F:43])([F:42])[C:14]1[CH:41]=[CH:40][C:17]([CH2:18][CH:19]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:46][C:47]([F:57])([F:56])[C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Br)=[CH:50][CH:49]=1.CCOCC>CN(C=O)C>[C:9]([O:8][P:6]([C:13]([F:43])([F:42])[C:14]1[CH:41]=[CH:40][C:17]([CH2:18][C:19]([CH2:52][C:51]2[CH:50]=[CH:49][C:48]([C:47]([F:46])([F:56])[F:57])=[CH:55][CH:54]=2)([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:16][CH:15]=1)([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(Cc2ccc(C(F)(F)F)cc2)(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
To a solution of the product from Example 18, Step 1 (94 mg, 0.15 mmol) in DMF (2 mL) at 0° C. was added NaH (5.5 mg, 80% in oil). After 15 min., 4-(trifluoromethyl)benzyl bromide (44 mg, 0.18 mmol) was added. After 2 h at 0° C., the mixture was given a standard aqueous/Et2O work-up, and the residue was purified by flash chromatography (1:10 EtOAc/hexane) to give a syrup (53 mg).
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH2:14][CH2:15][O:16]C)[C:12](=[O:18])[N:11]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][N:24]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[CH2:23][CH2:22]4)[CH:8]3[N:9]=2)=[C:5]([C:34]2[O:35][CH:36]=[CH:37][CH:38]=2)[N:4]=[CH:3]1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH2:14][CH2:15][OH:16])[C:12](=[O:18])[N:11]([CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][N:24]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[CH2:25][CH2:26]4)[CH:8]3[N:9]=2)=[C:5]([C:34]2[O:35][CH:36]=[CH:37][CH:38]=2)[N:4]=[CH:3]1
Reactant: COCCN1C(=O)N(CCN2CCN(c3ccc(F)cc3)CC2)C2N=C3C(=C(c4ccco4)N=CN3N)N21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NN1C=NC(c2ccco2)=C2C1=NC1N(CCN3CCN(c4ccc(F)cc4)CC3)C(=O)N(CCO)N21
Temperature: 25 °C
Reaction time: 20 h
Yield: 10.3 %

Procedure:
To a solution of compound 5-amino-3-[2-[4-(4-fluorophenyl)piperazin-1-yl]ethyl]-8-(2-furyl)-1-(2-methoxyethyl)-[1,2,4]triazolo[5,1-f]purin-2-one (Example I2) (0.050 g, 0.095 mmol), in DCM (3 ml) was added BBr3 (0.1 ml, 0.105 mmol) drop wise at 0° C. and stirred at 25° C. for 20 hours. The reaction mixture was quenched with sat. NaHCO3 (25 ml) and extracted with DCM (3×20 ml). The crude product was purified by LCMS to obtain 5-Amino-3-[2-[4-(4-fluorophenyl)piperazin-1-yl]ethyl]-8-(2-furyl)-1-(2-hydroxyethyl)-[1,2,4]triazolo[5,1-f]purin-2-one (5 mg, 10%) as an off white solid
Reaction SMILES: [NH2:1][C:2]1[C:22]([Br:23])=[CH:21][C:5]2[C:6]([C:17]([NH:19][CH3:20])=[O:18])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.N1C=CC=CC=1>[Br:23][C:22]1[C:2]([NH:1][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:3][C:4]2[O:8][C:7]([C:9]3[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[CH:13][CH:14]=3)=[C:6]([C:17]([NH:19][CH3:20])=[O:18])[C:5]=2[CH:21]=1
Reactant: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(N)c(Br)cc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 6-amino-5-bromo-2-(4-cyanophenyl)-N-methylbenzofuran-3-carboxamide (300 mg, 0.80 mmol) in DCM (2 mL) and pyridine (2 mL) was stirred at room temperature and MsCl (278 mg, 2.4 mmol) was added dropwise. The reaction was stirred at room temperature for 8 h. The reaction was washed with 1N HCl and extracted with DCM, dried with Na2SO4 and concentrated to give 5-bromo-2-(4-cyanophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (260 mg, yield: 72%). MS (M+H)+: 448/450.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=[O:6].C(OC(Cl)=O)C(C)C.C(N(CC)CC)C.[CH2:43]([NH:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]>O1CCCC1>[CH2:62]([N:61]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH:8]1[C:12]2([CH3:27])[CH:11]([CH:16]3[CH:15]([CH2:14][CH2:13]2)[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([OH:25])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[CH3:1])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Yield: 93.8 %

Procedure:
Lithocholic acid (81) (7.1 g, 18.8 mmol) was sissolved in anhydrous tetrahydrofuran (60 mL). Isobutylchloroformate (2.6 g, 2.6 mL, 18.8 mmol) was added followed by the addition of triethylamine (3.84 g, 5.3 mL, 38 mmol) and dioctadecylamine (9.8 g, 18.77 g). The reaction mixture was brought to ambient temperature and allowed to stir over night. The reaction mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane (250 mL). The organic layer was washed with 5% sodium bicarbonate, 3% aqueous HCl and water. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to afford amide 82 (15.5 g) in 93% yield. This was used as such for the next step.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3]>O1CCCC1>[CH3:6][O:5][C:1](=[O:4])[C:2](=[CH2:3])[CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: C=CC(=O)OC
Solvent: C1CCOC1
Product: C=C(CCC(=O)OC)C(=O)OC
Reaction time: 8 h

Procedure:
To a solution of 2,8,9-triisopropyl-2,5,8,9-tetraaza-1-phosphabicyclo(3,3,3)indecane (4.62 g) in tetrahydrofuran (180 ml) was added dropwise a solution of methyl acrylate (40.5 ml) in tetrahydrofuran (20 ml) at room temperature, and then the mixture was stirred overnight. This reaction solution was concentrated under reduced pressure, and then diisopropyl ether, n-hexane and chloroform were added to the resulting residue, and the mixture was again concentrated under reduced pressure. To the precipitated solid was added diisopropyl ether, the mixture was stirred, and then the insoluble substance was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 to 4/1) to give the titled compound (19.2 g).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:7][C:8](=[O:18])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:4][CH:5]=[CH2:6].CO[C:21](OC)([CH3:23])[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl.CO>C1(C)C=CC=CC=1>[CH3:22][C:21]1([CH3:23])[N:7]([C:8](=[O:18])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C@@H:3]([CH2:4][CH:5]=[CH2:6])[CH2:2][O:1]1
Reactant: C=CC[C@@H](CO)NC(=O)CNC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC[C@H]1COC(C)(C)N1C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a suspension of 1,1-dimethylethyl (2-{[(1S)-1-(hydroxymethyl)-3-buten-1-yl]amino}-2-oxoethyl)carbamate D21 (37 g) in toluene (370 ml) stirred at 25° C. were added 2,2-bis(methyloxy)propane (370 ml, 3020 mmol) and p-toluenesulfonic acid monohydrate (3.7 g, 19.45 mmol). The reaction mixture was stirred at reflux (85° C. internal, oil bath 105° C.) for 1.5 hour (clear solution). The check by TLC (DCM/MeOH 95/5) showed the reaction to be completed. The solvent was evaporated to obtain a brown oil that was chromatographed (Biotage 75 L, silica, eluting with Cy/EtOAc 8/2, 7/3) to give the title compound D22 (30 g) as yellow oil. UPLC (Acid GEN_QC): rt=0.69 minutes, peak observed: 299 (M+1). C15H26N2O4 requires 298. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9 H) 1.54 (s, 3 H) 1.67 (s, 3 H) 2.30-2.49 (m, 2 H) 3.71-4.05 (m, 5 H) 5.04-5.22 (m, 2 H) 5.37-5.52 (m, 1 H) 5.65-5.81 (m, 1 H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([Cl:21])=[CH:19][C:18]([F:22])=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[C:18]([F:22])[CH:19]=1
Reactant: C#CCCc1nc2cc(F)cc(Cl)c2o1
Reactant: Brc1ccccn1
Product: Fc1cc(Cl)c2oc(CCC#Cc3ccccn3)nc2c1
Yield: 59.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (141 mg, 0.89 mmol) and 2-(but-3-ynyl)-7-chloro-5-fluorobenzo[d]oxazole (200 mg, 0.89 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 160 mg (0.53 mmol, 59%) of 7-chloro-5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orange solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][N:18]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]2[CH3:26])[CH:6]=[CH:5][N:4]=1.[SH:27][C:28]1[NH:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1>C(O)(C)C>[CH3:9][C:8]1[C:3]([CH2:2][S:27][C:28]2[NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[N:29]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][N:18]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]1[CH3:26]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(SCCCCSCCn2c([N+](=O)[O-])cnc2C)ccnc1CCl
Solvent: CC(C)O
Product: Cc1c(SCCCCSCCn2c([N+](=O)[O-])cnc2C)ccnc1CSc1nc2ccccc2[nH]1

Procedure:
2.5 g (6 mmol) of 2-chloromethyl-3-methyl-4-{4-[2-(2-methyl-5-nitroimidazol-1-yl)ethylthio]butylthio}-pyridine and 0.9 g (6 mmol) of 2-mercaptobenzimidazole are heated to reflux for 1 h in 25 ml of isopropanol. The mixture is then cooled in an ice bath and the precipitated solid is filtered off with suction. The solid is taken up in water and treated with saturated sodium hydrogen carbonate solution. The mixture is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated. The title compound crystallizes and is washed with a little methanol with stirring. M.p. 160°-162° C.; yield 0.62 g (20% of theory).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[CH2:15][CH2:16][CH2:17][N:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][CH2:21][C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]1=2)=[O:4].C(O)C.[OH-].[Na+].[ClH:38]>O.O1CCCC1>[ClH:38].[CH:29]1[C:20]2[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:18]([CH2:17][CH2:16][CH2:15][N:6]3[CH:5]([C:3]([OH:4])=[O:2])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)[C:19]=2[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)C1Cc2ccccc2CN1CCCN1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1Cc2ccccc2CN1CCCN1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 22 h
Yield: 75 %

Procedure:
A mixture of the above ester (0.80 g, 0.0019 mol), ethanol (5 ml), tetrahydrofuran (5 ml) and 4 N sodium hydroxide (4 ml) was stirred at room temperature for 22 h. Water (50 ml) and concentrated hydrochloric acid (2 ml) were added and the mixture was extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo. This gave 0.8 g of a solid, which was triturated and washed with ethyl acetate (2×5 ml). Drying in vacuo, afforded 0.6 g (75%) of the title compound as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:8]=[C:9]2[C:12]#[N:13])=[CH:4][CH:3]=1.C1C(=O)N([Br:29])C(=O)C1>C1COCC1>[Br:29][C:11]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[C:9]([C:12]#[N:13])=[CH:8][C:7]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[CH:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2cc(C#N)c3cc(O)ccc3c2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C#N)c3c(Br)c(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 7-hydroxy-3-(4-methoxyphenyl)-1-naphthonitrile (0.160 g, 0.58 mmol) with NBS (0.12 g, 0.70 mmol) in THF (10 mL) according to method C to yield 0.080 g (39%) of a yellow solid: mp 145-146° C.; 1H NMR (DMSO-d6): δ 3.83 (3H, s), 7.08 (2H, d, J=8.79 Hz), 7.42 (1H, d, J=8.79 Hz), 7.84 (2H, d, J=8.79 Hz), 8.04 (1H, d, J=8.79 Hz), 8.42 (1H, d, J=1.95 Hz), 8.53 (1H, d, J=1.95 Hz), 11.21 (1H, s); MS (ESI) m/z 354/356 (M+H+; MS (ESI) m/z 352/354 (M−H)−.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Cl:5][C:6]([Cl:13])([Cl:12])[CH2:7][CH2:8][C:9](Cl)=[O:10].C(N(CC)CC)C>C1CCCCC1>[Cl:5][C:6]([Cl:13])([Cl:12])[CH2:7][CH:8]1[C:2]([CH3:4])([CH3:3])[CH2:1][C:9]1=[O:10]
Reactant: C=C(C)C
Reactant: O=C(Cl)CCC(Cl)(Cl)Cl
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)C1CC(Cl)(Cl)Cl
Reaction time: 4 h

Procedure:
261 g of isobutylene is injected into a 1 liter autoclave containing 49 g (0.23 mol) of 4,4,4-trichlorobutyric acid chloride in 280 ml of cyclohexane. A solution of 28.3 g (0.28 mol) of triethylamine in 233 ml of cyclohexane is pumped in at 70° C. in the course of 4 hours. The reaction mixture is afterwards held at 70° C. for a further 4 hours. The precipitated hydrochloride of the triethylamine is filtered off; the filtrate obtained is washed with dilute hydrochloric acid and then with water, dried over sodium sulphate and concentration by evaporation. Distillation of the residue yields 2-(2',2',2'-trichloroethyl)-3,3-dimethylcyclobutanone as a clear liquid, b.p. 118°-122° C./14 mm Hg.
Reaction SMILES: C([S:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=S)OCC.[OH-].[K+]>C(O)C>[C:9]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]=[CH:11][CH:12]=[C:7]([SH:6])[CH:8]=1
Reactant: CCOC(=S)Sc1cccc(-c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Sc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 113.8 %

Procedure:
To a solution of 52a (1.1 g, crude compound) in ethanol (8 mL) was added potassium hydroxide (2.1 g, 12 mL) and heated to reflux for overnight. The solution was cooled to RT and the ethanol was evaporated under reduced pressure. The residue was dissolved in water and washed with diethyl ether (10 mL). The aqueous layer was acidified with 2 N HCl and extracted with diethyl ether (3×50 mL). The organic extracts were washed with water (50 mL), brine (50 mL), dried over MgSO4, filtered and evaporated under reduced pressure to afford 0.85 g (77.3%) of crude biphenyl-3-thiol product (overall, 3 steps). Into a round-bottomed flask, stirred magnetically, were placed 0.1 g (1.04 mmol) of sodium tert-butoxide and 83 mg of copper iodide (0.43 mmol). After the reaction vessel was sealed, 0.13 g (0.71 mmol) of 4-methoxybenzenethiol and 0.19 g (0.65 mmol) of 5-iodo-1,2,3-trimethoxybenzene in 3.0 mL of toluene were injected through the septum. The reaction mixture was heated for overnight at 110° C. Purification was performed by flash chromatography, and an amorphous solid was obtained (40% yield). 1H NMR (500 MHz, CDCl3) δ 7.54-7.52 (m, 3H), 7.44-7.41 (m, 3H), 7.37-7.33 (m, 2H), 7.23 (s, br, 1H), 6.69 (s, 2H), 3.86 (s, 3H), 3.80 (s, 6H). MS (ESI) m/z 353.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN([C:27]([O:31][N:32]1N=NC2C=CC=N[C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNOC>C1COCC1.[NH4+].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12](=[O:14])[N:32]([O:31][CH3:27])[CH3:33])[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
To a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (Alfa, 5.0 g, 24.9 mmol) in THF (80 mL) was added DIEA (9.55 mL, 54.7 mmol) and HATU (11.34 g, 29.8 mol) and the reaction mixture was stirred at ambient temperature for 1.5 h. N,O-dimethylhydroxylamine (1.82 g, 29.8 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with aqueous NH4Cl (100 mL). The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 15% EtOAc in petroleum ether) to give 3-(methoxy-methyl-carbamoyl)-azetidine-1-carboxylic acid tert-butyl ester (6.0 g, 99.0%). 1H NMR (DMSO-d6, 400 MHz): δ 4.02 (m, 4H), 3.71 (m, 1H), 3.63 (s, 3H), 3.11 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.C1(C)C(C)=CC=CC=1.[NH2:15][C:16]1[S:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][N:20]=1>CCCCCCC>[C:21]([C:18]1[S:17][C:16]([NH:15][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])=[N:20][N:19]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)(C)c1nnc(N)s1
Solvent: Cc1ccccc1C
Solvent: CCCCCCC
Product: CC(=O)CC(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A 2-liter reaction flask with appropiate fittings was charged with 33.6 g (0.4 mole) of diketene, 965 ml of xylene and 59.7 g (0.38 mole) of 2-amino-5-tert-butyl-1,3,4-thiadiazole. The stirred mixture was heated to 70° at which time all solids had dissolved. After 1 hour, the solution was cooled and added to 2500 ml of chilled heptane. Product precipitation was judged complete after two hours. The solids were collected on a vacuum filter and air dried. There was obtained 54 g (58.9%) of white product, m.p. 166°-68°. N.M.R. (CDCl3 -dimethyl-d6 sulfoxide) ∂ 1.5 [C(CH3)3 ], 2.0 (CH3, enol), 2.3 (CH3, keto), 3.6 (CH2), 5.4 (CH, enol).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][CH2:13][C:14]([OH:16])=O)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:22]1[C:30]2[N:29]=[CH:28][NH:27][C:26]=2[C:25](=[O:31])[NH:24]/[C:23]/1=[N:32]\[NH2:33])[CH2:18][CH2:19][CH2:20][CH3:21].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[O:31]=[C:25]1[NH:24]/[C:23](=[N:32]\[NH:33][C:14](=[O:16])[CH2:13][CH2:12][C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]=2)/[N:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:30]2[N:29]=[CH:28][NH:27][C:26]1=2
Reactant: O=C(O)CCc1nnc(-c2ccccc2)o1
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCn1/c(=N/NC(=O)CCc2nnc(-c3ccccc3)o2)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
The mixture of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)propanoic acid (500 mg, 20 mmol), (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (480 mg, 0.0020 mol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (980 mg, 22 mmol), 4-dimethylaminopyridine (100 mg, 10 mmol), and N,N-diisopropylethylamine (0.73 mL, 42 mmol) in DMF (30 mL) was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate three times. The combined organic layers were washed by brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography to yield the desired product (485 mg, 48.5%). LCMS calculated for C21H25N8O3(M+H): 437.2; found 437.2.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][N:7](O)[C:8]([NH2:10])=[NH:9].[Na].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]=[C:22]([C:26]([O:28]C)=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CC(C)([O-])C.[K+]>C(O)C.O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]=[C:22]([C:26]2[O:28][N:10]=[C:8]([NH:7][CH3:6])[N:9]=2)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)C1=CCCN(C(=O)OC(C)(C)C)C1
Reactant: CN(O)C(=N)N
Agent: CC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CNc1noc(C2=CCCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
N-Methyl-hydroxyguanidine sulphate (17.0 g, 0.061 mol) was stirred with 4A molecular sieves (20 g) in ethanol (80 mL) under a nitrogen atmosphere for 2 hours. Sodium (2.8 g, 0.122 mol) was added in portions then the mixture was stirred at 50° C. for 1 hour. A solution of methyl 1-t-butyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate (3.0 g, 0.012 mol) in ethanol (40 mL) was added and the reaction mixture was stirred whilst heating under reflux for 4 hours. The mixture was cooled, filtered, evaporated to dryness. The residue was dissolved in tetrahydrofuran (40 mL), treated with potassium t-butoxide (1.35 g, 0.012 mol) and stirred for 3 hours. Water (50 mL) was added and the mixture extracted with dichloromethane (5×50 mL). The combined organics were dried (sodium sulphate) then evaporated to dryness to give a yellow gum which was purified by column chromatography on silica using dichloromethane/methanol (80:1) afford the product as a pale yellow gum (1.10 g, 33%). (HRMS, Found: M+, 280.1530, C13H20N4O3 requires M, 280.1535). (Found: C, 54.70; H, 7.29; N, 18.91. C13H20N4O3 requires C, 55.70; H, 7.19, N, 19.99%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C:8](=[C:9]4[C:14](=[CH:15][CH:16]=3)[CH:13]=[CH:12][CH:11]=[CH:10]4)[CH:7]=[CH:6][C:5]=2[CH:4]=1.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:4]1[C:5]2[CH:6]=[CH:7][C:8]3[C:17](=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][CH:12]=[CH:13]4)[C:18]=2[CH:19]=[CH:20][C:3]=1[CH:2]=[O:1]
Reactant: OCc1ccc2c(ccc3c4ccccc4ccc23)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(ccc3c4ccccc4ccc23)c1
Yield: 87.9 %

Procedure:
2-Hydroxymethylchrysene (20C, 8.0 g, 0.031 mol) in CH2Cl2 (2.5 L) was treated with BaMnO4 (Aldrich, 15.9 g, 0.062 mol) and refluxed for 12 h. The reaction mixture was filtered, and concentrated to give a solid, which was then passed through a plug of SiO2 (500 g) using PhCH3 as the eluting solvent. The appropriate fractions were combined and the volume reduced to 75 mL to afford 6.98 g (88%) of chrysene-2-carbaldehyde mp 215°-216.5°, (C, H).