Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:14][CH2:13][CH2:12][CH2:11][C:4]=2[N:5]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.C(OC([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=O)(C)(C)C>C(O)CC(C)C>[ClH:1].[ClH:1].[CH3:9][CH:8]([C:6]1[N:7]=[C:2]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:3]2[S:14][CH2:13][CH2:12][CH2:11][C:4]=2[N:5]=1)[CH3:10]
Reactant: CC(C)c1nc(Cl)c2c(n1)CCCS2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)CCO
Product: CC(C)c1nc2c(c(N3CCNCC3)n1)SCCC2
Product: Cl

Procedure:
A solution of 4-chloro-7,8-dihydro-2-(1-methylethyl)-6H-thiopyrano[3,2-d]pyrimidine (from Table I) (2.8 g) and N-tert-butoxycarbonylpiperazine (5.0 g) in isoamyl alcohol (50 ml) was heated at reflux for 1 hour, cooled, filtered and the solvent distilled at reduced pressure. The residue was dissolved in ether, washed with H2O and brine, dried over magnesium sulfate and evaporated in vacuo. To the residue was added trifluoroacetic acid (40 ml) which after 1 hour was distilled at reduced pressure. The residue was treated with ice and excess 10N sodium hydroxide, extracted into CH2Cl2, washed with water and brine and dried over K2CO3. The CH2Cl2 was distilled at reduced pressure and the residue was dissolved in ethanol (30 ml), treated with 10N ethanolic HCl (3 ml) and ether (30 ml) to give the title compound which melts at 256° to 258° C. after recrystallization from 2-propanol-ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=2[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:6](=[O:9])[CH2:7]N=1.[CH3:24]C(C)([O-])C.[K+].[Br:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br>C1COCC1>[Br:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][CH:7]1[C:6](=[O:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:4]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:3]=2[C:2]([Cl:1])=[CH:24]1
Reactant: COc1ccc(CN2C(=O)CN=C(Cl)c3cc(Cl)ccc32)cc1
Reactant: CC(C)(C)[O-]
Reactant: BrCc1ccccc1Br
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3Br)C=C(Cl)c3cc(Cl)ccc32)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of (E)-5,7-dichloro-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.45 g, 1.28 mmol) in anhydrous THF (20 mL), was added at −78° C. under a N2 atmosphere, a solution of potassium tert-butoxide (1 M in THF, 1.54 mL, 1.54 mmol). After completion of the addition the reaction mixture was stirred for ½ h at −78° C. and a solution of 2-bromobenzylbromide (0.386 mL, 1.54 mmol) in THF (5 mL) was added at −78° C. drop-wise over 15 minutes. The reaction mixture was stirred at −78° C. for 2 more hours and then the temperature was raised to room temperature. The reaction mixture was left at room temperature overnight under a N2 atmosphere. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4) and evaporated in vacuo. The crude material was purified by flash column chromatography (eluted with 20% EtOAc in Hexane) to give (E)-3-(2-bromobenzyl)-5,7-dichloro-1-(4-methoxybenzyl)-1H-benzo[b]azepin-2(3H)-one (0.49 g, 74%) as a pale solid. 1H NMR (400 MHz, DMSO-d6) δ 3.65 (s, 3H), 4.06-4.10 (m, 2H), 4.86 (d, 1H), 5.39 (d, 1H), 4.79 (d, 2H), 6.92 (d, 2H), 7.12-7.39 (m, 3H), 7.54-7.56 (m, 1H), 7.67-7.82 (m, 3H). MS m/z 519.20 [M+1].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[K+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH-:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1>CN1CCCC1=O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=2)(=[O:20])=[O:21])=[CH:17][CH:18]=1
Reactant: [NH-]S(=O)(=O)c1ccc(Cl)cc1
Reactant: CNc1nc(Cl)cc(Cl)n1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(Cl)cc2)n1
Yield: 84.6 %

Procedure:
0.39 g (0.0022 mol) of (4,6-dichloro-pyrimidin-2-yl)-methylamine and 1.0 g (0.0044 mol) of 4-chloro-benzene-sulfonamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 150° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water and extracted. The aqueous phase was saturated with sodium chloride, evaporated briefly in a vacuum, made acid with 4N HCl and extracted with dichloromethane. The two extracts were combined and chromatographed over silica gel with cyclohexane/ethyl acetate 1:1 as the eluent. There was obtained 0.62 g (85%) of 4-chloro-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals. m.p. 196-198° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8].S(=O)(=O)(O)O.O.[CH3:18]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:18])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8]
Reactant: CO
Reactant: CCc1sc(C(=O)O)cc1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1sc(C(=O)OC)cc1Br
Temperature: 50 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of 4-bromo-5-ethyl-2-thiophenecarboxylic acid (1 g, 4.25 mmol) in methanol (21.27 ml) was added sulfuric acid (0.23 mL, 4.25 mmol). The resulting solution was stirred at 50° C. for 48 h. H2O (50 mL) was added and the reaction was cooled to 0° C. in an ice-bath. The pH was adjusted to ˜12 and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification providing methyl 4-bromo-5-ethyl-2-thiophenecarboxylate (1.060 g, 4.25 mmol, 100% yield): LCMS (ES) m/e 248, 250 (M, M+2)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([CH3:14])=[N:9]2)[N:5]=[C:4]([CH3:15])[N:3]=1.[IH:16]>O>[CH3:14][C:10]1[N:11]=[C:12]([CH3:13])[N:8]([C:6]2[CH:7]=[C:2]([I:16])[N:3]=[C:4]([CH3:15])[N:5]=2)[N:9]=1
Reactant: I
Reactant: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1
Solvent: O
Product: Cc1nc(I)cc(-n2nc(C)nc2C)n1
Temperature: 70 °C

Procedure:
To a mixture of 4-chloro-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine (2.00 g, 8.9 mmol), KI (4.44 g, 26.8 mmol) was added 57% aq. HI solution (20 mL, 89.2 mmol). After heating at 70° C. for 5 min, water (20 mL) was added to the reaction mixture. The white solid was filtered, rinsed with water, and dried under vacuum to give Intermediate 2 as a white solid. 1H NMR (400 MHz, DMSO) δ 8.06 (s, 1H), 2.78 (s, 3H), 2.62 (s, 3H), 2.30 (s, 3H). MS: m/z=316.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([O:20][CH3:21])[N:3]=1.[C:22](OCC(Cl)(Cl)Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)(=O)CCCC.C(Cl)(O)C(Cl)Cl>N1C=CC=CC=1.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][O:19][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([O:20][CH3:21])[N:3]=1
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCCCC(=O)OCC(Cl)(Cl)Cl
Agent: CCCCC(=O)Cl
Agent: OC(Cl)C(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCC(=O)OC[C@H]1O[C@@H](n2cnc3c(OC)nc(N)nc32)[C@@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 24 h

Procedure:
2-Amino-6-methoxy-9-β-D-arabinofuranosyl-9H-purine (1.0 g, 3.2 mmol) was suspended in 40 ml of pyridine that contained 300 μL of H2O and 2.0 mL of trichloroethyl valerate (Trichloroethyl valerate was synthesized by addition of 36 g of valeryl chloride (Aldrich) over 30 minutes to 45 g of trichloroethanol (Aldrich) in 50 mL of pyridine at 0° C. The product was purified by successive washing with 2×250 ml aliquots of H2O, 5% NaHCO3, and H2O. 1H-NMR (200 MHz, CDCl3): δ4.74 (s, 2H, Cl3CH2 --), 2.48 (t, 2H, J=7.6 Hz, CH3CH2CH2CH2CO2 --), 1.68 (m, 2H, CH3CH2CH2CH2CO2 --), 1.53 (M, 2H, CH3CH2CH2CH2CO2 --), 0.93 (t, 3H, J=7.2 Hz, CH3CH2CH2CH2CO2 --)). The reaction was initiated with 0.100 g of subtilisin (Sigma Chemical Co., St. Louis, Mo., P-5380, lot #38F-0356), which had been activated by dissolving 1 g of the enzyme in 20 ml of 0.1M potassium phosphate at pH 7.8 and lyophilizing to dryness. After stirring for 24 hours at 40° C., the reaction was quenched by filtering off the enzyme and the solvent was removed in vacuo. The crude product was purified by chromatography on a 4.5×25 cm silica gel column with CH2Cl2 :CH3OH (90:10) as the eluant. Product fractions were pooled and lyophilized from water to yield 0.85 g of the desired product as a white powder; m.p. 105° C.; TLC Rf =0.39 (silica gel; CH2Cl2:CH3OH (90:10)); UV λmax (ε;, mM- 1 cm-1) at pH 7.0, 279 nm (9.3); MS (Cl) 382 (M+1), 280 (M-C5H9CO2). 1H-NMR (200 MHz, DMSO-d6): δ7.83 (s, 1H, H8), 6.45 (s, 2H, 2-NH2), 6.15 (d, 1H, J=3.7 Hz, H1 '), 5.76(d, 1H, J=4.2 Hz, 2'--OH), 5.65 (d, 1H, J=3.5 Hz, 3'OH), 4.28 (m, 2H, H2' and H3'), 4.08(m, 2H H5'), 3.94 (s, 3H, --OCH3) 3.92 (m, 1H, H4'), 2.29 (t, 2H, J=7.1 Hz, CH3CH2CH2CH2CO2 --), 1.49(m, 2H, CH3CH2CH 2 CH2CO2 --) 1.28 (m, 2H CH3CH2CH2CH2CO2 --), 0.83 (t, 3H, J=7.2 Hz, CH3CH2CH2CH2CO2 --). Anal. Calcd. for C16H23N5O6.0.36 H2O: Calcd: C, 49.54; H, 6.16; N,18.05. Found: C, 49.52; H,6.15; N, 18.10.
Reaction SMILES: [O:1]=[C:2]1[NH:15][C:5]2=[N:6][CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=[C:4]2[CH2:3]1.[C:16]([O:19][CH:20](OCC)OCC)(=O)[CH3:17].C(OCC)C>C(O)(=O)C>[CH2:16]([O:19]/[CH:20]=[C:3]1\[C:2](=[O:1])[NH:15][C:5]2[C:4]\1=[CH:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][N:6]=2)[CH3:17]
Reactant: CCOC(=O)c1cnc2c(c1)CC(=O)N2
Reactant: CCOC(OCC)OC(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCO/C=C1\C(=O)Nc2ncc(C(=O)OCC)cc21
Temperature: 110 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
Ethyl 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.040 g, 0.19 mmol) and diethoxymethyl acetate (0.16 mL, 0.97 mmol) were combined and dissolved in acetic acid (1 mL). The reaction was warmed to 110° C. and stirred at this temperature for 1 hour. The reaction was cooled to room temperature, and diethyl ether was added to precipitate the title compound as a beige solid that was collected by filtration (35 mg, 69% yield). 1H NMR 400 MHz (DMSO-d6): δ 11.30 (s, 1H); 8.58 (s, 1H); 8.05 (s, 1H); 7.93 (s, 1H); 4.44 (m, 2H); 4.28 (m, 2H); 1.35 (m, 3H); 1.28 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:12])[C@@H:9](O)[CH3:10])[CH:5]=[CH:6][CH:7]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:44][C:45]([CH3:49])([CH3:48])[CH2:46][OH:47]>C(Cl)Cl.CC#N.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]2([OH:12])[O:47][CH2:46][C:45]([CH3:49])([CH3:48])[NH:44][C@@H:9]2[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: C[C@H](O)C(=O)c1cccc(Cl)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1NC(C)(C)CO[C@]1(O)c1cccc(Cl)c1
Temperature: -50 °C

Procedure:
Following the procedure described for (2S,3S)-4a, a sample of (S)-1-(3-Chlorophenyl)-2-hydroxypropan-1-one ((S)-10a, 4.5 g, 0.024 mol), was dissolved in CH2Cl2 (75 mL) and treated with Proton sponge (6.3 g) and cooled to −50° C. Next, triflic anhydride (4.5 mL, 32 mmol) was added slowly, and the reaction mixture was stirred at 0° C. for an additional hour. The resulting orange slurry was transferred by syringe to another flask containing a solution of 2-amino-2-methyl-1-propanol, (4.7 g, 0.052 mol) in CH3CN. After purification, 3.3 g (78%) of the (2R,3R)-4a was isolated and converted to 2.7 g of the Hemi-L-tartrate salt (>99% ee): mp 128-131° C.; [α]23D −13.0° (c 0.79, CH3OH). Characterization data is similar to data reported in Fang, Q. K. et al., Tetrahedron: Asymmetry 2000, 11, 3659-3663.
Reaction SMILES: [IH:1].[CH3:2][O:3][C:4](=[O:36])[C@H:5]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22](SC)=[NH:23])=[CH:18][CH:17]=2)[CH:9]=1.C([O-])(=O)C.[NH4+:41].CCOCC.C(OC(C)C)(C)C>CO>[IH:1].[CH3:2][O:3][C:4](=[O:36])[C@H:5]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22](=[NH:41])[NH2:23])=[CH:18][CH:17]=2)[CH:9]=1
Reactant: COC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c1cccc(NC(=O)c2ccc(C(=N)SC)cc2)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: I
Solvent: CCOCC
Solvent: CC(C)OC(C)C
Solvent: CO
Product: COC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c1cccc(NC(=O)c2ccc(C(=N)N)cc2)c1
Yield: 71 %

Procedure:
A solution of 3-(t-butoxycarbonyl)-N-[m-[p-[1-(methylthio)formimidoyl]benzamido]benzoyl]-L-alanine methyl ester hydroiodide in methanol is reacted with ammonium acetate in an analogous manner to that described in Example 33 B) h). There is obtained in 71% yield N-[m-(p-amidinobenzamido)benzoyl]-3-(t-butoxycarbonyl)-L-alanine methyl ester hydroiodide in the form of a colourless solid, m.p. 118°-120° C. (ether/isopropyl ether), MS: 469 (M+1)+.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:15]=[C:14]([CH2:16][CH2:17][C@@:18]([CH3:33])([S:29]([CH3:32])(=[O:31])=[O:30])[C:19]([NH:21][O:22]C2CCCCO2)=[O:20])[O:13][N:12]=1>O1CCOCC1.ClCCl.O>[F:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:15]=[C:14]([CH2:16][CH2:17][C@@:18]([CH3:33])([S:29]([CH3:32])(=[O:31])=[O:30])[C:19]([NH:21][OH:22])=[O:20])[O:13][N:12]=1
Reactant: COc1cccc(-c2cc(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)on2)c1F
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2cc(CC[C@](C)(C(=O)NO)S(C)(=O)=O)on2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
Hydrochloric acid (4.0 M in 1,4-dioxane, 0.49 mL, 1.9 mmol, 4.0 equiv) was added to a solution of (2R)-4-[3-(2-fluoro-3-methoxyphenyl)isoxazol-5-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.23 g, 0.49 mmol, 1.0 equiv) in 1,4-dioxane-dichloromethane-water (2:2:1, 5 mL), and the reaction was allowed to stir at room temperature for 2 h. The solvent was removed under reduced pressure, and the resulting crude material was purified by flash chromatography (30 g C18 reverse phase column, 5-60% gradient acetonitrile in water) to provide (2R)-4-[3-(2-fluoro-3-methoxyphenyl)isoxazol-5-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide as a light brown solid (0.09 g, 48%). MS (LCMS) m/z 387.1 (M+1). 1H NMR (400 MHz, METHONAL-d4) δ1.67 (s, 3H) 2.20-2.38 (m, 1H) 2.80 (s, 2H) 2.95-3.09 (m, 1H) 3.10 (s, 3H) 3.94 (s, 3H) 6.68 (d, J=3.12 Hz, 1H) 7.22 (dd, J=5.95, 1.17 Hz, 2H) 7.33-7.51 (m, 1H).
Reaction SMILES: Cl.Cl.[N+:3]([C:6]1[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=3[CH:23]=2)[CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]([CH3:35])[N:26]=1.C(N(C(C)C)CC)(C)C.O>CN1C(=O)CCC1>[CH3:35][C:27]1[N:26]=[C:25]([N:19]2[CH2:18][C:17]3[CH:23]=[C:13]([C:11]4[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:3]([O-:5])=[O:4])[CH:12]=4)[CH:14]=[CH:15][C:16]=3[O:22][CH2:21][CH2:20]2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1
Reactant: Nc1ccc(-c2ccc3c(c2)CNCCO3)cc1[N+](=O)[O-]
Reactant: Cc1nc(Cl)c2ccccc2n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCOc3ccc(-c4ccc(N)c([N+](=O)[O-])c4)cc3C2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89 %

Procedure:
A solution of 2-nitro-4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)aniline dihydrochloride (323 mg, 1.0 mmol), 4-chloro-2-methylquinazoline (179 mg, 1.0 mmol), and diisopropylethylamine (700 uL, 4.0 mmol) in NMP (11 mL) was heated to 90° C. and stirred for 40 min. After cooling to rt, water was added to the reaction mixture. The orange precipitate formed was collected by filtration and then dried to provide 4-[4-(2-methylquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-2-nitroaniline (380 mg, 0.89 mmol, 89% yield) as a bright orange powder. MS (EI) for C24H21N5O3: 428 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]([OH:25])=O)=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:27]>C1(C)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]([Cl:27])=[O:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(=O)O)nn2-c2ccc(F)cc2)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc(C(=O)Cl)nn2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.5 %

Procedure:
A mixture of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylic acid (1.1 g) and phosphorus pentachloride (0.67 g) in toluene (16 ml) and tetrahydrofuran 9 ml) was stirred at ambient temperature for 2 hours. The insoluble material was filtered and the filtrate was concentrated to give an oil of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonyl chloride (1.37 g).
Reaction SMILES: [CH2:1]([N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH3:18])[CH:13]=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9])[CH2:2][CH2:3]CC=C.C[N+]1([O-])CC[O:24]CC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:36]([OH:40])(C)([CH3:38])[CH3:37]>[Os](=O)(=O)(=O)=O.O.CC(C)=O>[OH:40][CH:36]([CH2:38][OH:24])[CH2:37][CH2:3][CH2:2][CH2:1][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH3:18])[CH:13]=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1cnc2c1c(=O)n(CCCCC(O)CO)c(=O)n2C
Reaction time: 48 h
Yield: 62 %

Procedure:
Six drops of 2.5% osmium tetraoxide in t-butanol were added to a mixture of 1-(5-hexenyl)-3,7-dimethylxanthine (1.07 g, 4.1 mmol), as prepared above and N-methylmorpholine-N-oxide (1.44 g, 12.3 mmol) in water (20 ml) and acetone (10 ml). After stirring the resulting mixture for 48 hours, the mixture was treated with 20% aqueous sodium dithionite solution (20 ml). After 2 minutes, the mixture was extracted with three 30 ml aliquots of a 25% ethanol-dichloromethane solution. The combined extracts were dried over magnesium sulfate and the solvent was evaporated under vacuum, leaving 750 mg of a white powder, 1-(5,6-dihydroxyhexyl)-3,7-dimethylxanthine (2.53 mmol, 62% yield).
Reaction SMILES: [CH3:1][N:2](C)[C:3](N)=[O:4].C(OC(=O)C)(=[O:9])C.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1>[CH3:1][N:2]1[C:17]([CH3:16])=[CH:18][C:19](=[O:9])[N:14]([CH3:15])[C:3]1=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Reactant: CN(C)C(N)=O
Agent: CN(C)c1ccncc1
Product: Cc1cc(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N,N-dimethyl urea (10.0 g, 113.588 mmol) and 4-dimethylamino pyridine (13.873 g, 113.588 mmol) in dry pyridine (30 ml), acetic anhydride (32.20 ml, 340.67 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was quenched into 2 N HCl (250 ml) and extracted with chloroform (2×250 ml). The organic layer was washed with 1 N HCl (100 ml), sodium bicarbonate solution (75 ml), brine (75 ml) and dried (Na2SO4). The solvent was evaporated under reduced pressure to obtain 10.25 g of the product as a yellow solid; 1H NMR (300 MHz, CDCl3) δ 2.24 (s, 3H), 3.33 (s, 3H), 3.40 (s, 3H), 5.62 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][NH:9][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CBr
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)CNCCc1ccccc1
Reaction time: 18 h
Yield: 124.2 %

Procedure:
To a stirred solution of 2-phenylethylamine (9.68 g, 40 mmol) in toluene (50 mL) was added methyl bromoacetate (6.12 g, 20 mmol) dropwise at room temperature and was left stirring for 18 hours. The reaction mixture was filtered before removing the solvent in vacuo and the residue was purified by chromatography over silica gel to yield 4.8 g (61%) of the title compound as an oil. NMR (250 MHz, CDCl3) δ(1H, s), 2.92 (4H, m), 3.43 (2H, s), 3.71 (3H, s), 7.27 (5H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11](Cl)[C:12](Cl)=[C:13](Cl)[C:14]=1Cl)[C:8]([OH:10])=[O:9].[CH2:20]([SH:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11]([S:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:12]([S:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:13]([S:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:14]=1[S:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(O)=NCCO
Reactant: CCCCCCCCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCSc1c(SCCCCCCCCCC)c(SCCCCCCCCCC)c(C(O)=NCCO)c(C(=O)O)c1SCCCCCCCCCC

Procedure:
2 g (6.08 millimols) of tetrachlorophthalic acid N-2-hydroxyethylimide, 5.30 g (30.4 millimols) of n-decanethiol, 6.30 g (45.6 millimols) of potassium carbonate and 20 ml of N,N-dimethylformamide are stirred at 25° C. for 7 hours. The mixture is acidified and extracted with methylene chloride. After recrystallisation from n-hexane at 0° C., 3.75 g (70% of theory) of the title compound are obtained; melting point 57°-8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[C:6]([N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].CO[C:25](OC)([CH3:27])[CH3:26]>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][C:25]1([CH3:27])[O:12][CH2:11][CH:10]([NH:9][C:7]2[C:6]([N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH2:13][O:14]1
Reactant: COC(C)(C)OC
Reactant: COc1ccc([N+](=O)[O-])c(NC(CO)CO)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(NC2COC(C)(C)OC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
2-{[6-(Methyloxy)-3-nitro-2-pyridinyl]amino}-1,3-propanediol (53.93 g, 228.7 mmol) was stirred in 2,2-dimethoxypropane (900 ml) under argon and p-toluenesulphonic acid monohydrate (1.00 g) was added. The mixture was stirred at room temperature overnight to give a clear yellow solution. This was with diluted with DCM (1 L) and the resulting solution was treated with saturated aqueous NaHCO3 (20 ml) and solid NaHCO3 (20 g) with vigorous stirring (effervescence). The mixture was vigorously stirred for 20 minutes, then the remaining water was absorbed by addition of anhydrous Na2SO4. The mixture was filtered with suction and the solids were washed with DCM (500 ml). The combined filtrate plus washings were evaporated under reduced pressure to give a yellow solid which was stirred with petroleum ether (40-60°) over the weekend. The solid was isolated by filtration with suction, washed with petroleum ether (40-60°) and air-dried to give the title compound as a bright yellow solid (57.83 g, 92%).