Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([OH:16])=O)[N:7]=3.[C:19]([O:23][C:24]([NH:26][NH:27][CH:28]([CH3:30])[CH3:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:19]([O:23][C:24]([NH:26][N:27]([C:14]([C:8]1[N:7]=[C:6]2[N:10]([CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Br:1])[CH:18]=[CH:17][C:5]=32)[CH:9]=1)=[O:16])[CH:28]([CH3:30])[CH3:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)NNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)OC(C)(C)C)C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reaction time: 8 h
Yield: 104.7 %

Procedure:
To a mixture of 8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (1.92 g, 6.2 mmol) and N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester (1.30 g, 7.5 mmol) in DMF (20 mL) at 0° C. was added DIPEA (2.70 mL, 15.5 mmol) and HATU (3.54 g, 9.3 mmol). The reaction mixture was stirred for 7 h at RT before the addition of DMF (40 mL) and stirring overnight. The reaction mixture was concentrated in vacuo and the resultant residue partitioned between DCM and water. The aqueous phase was extracted with DCM (×2) before the combined organic extracts were washed sequentially with 10% citric acid solution, saturated sodium bicarbonate solution then brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-90% ethyl acetate in cyclohexane) to give N′-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl)-N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester as a white solid (3.02 g, quantitative yield). LCMS RT=4.76 min, [M+H]+=465/467. 1H NMR 400 MHz (DMSO-d6) δ: 8.62 (1 H, s), 8.40 (1 H, d, J=8.59 Hz), 7.69 (1 H, s), 7.23-7.22 (2 H, m), 4.81 (1 H, s), 4.44 (4 H, s), 1.32 (9 H, s), 1.13 (6 H, d, J=6.64 Hz)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].C1(C)C=CC(S([N:20]=[N+:21]=[N-])(=O)=O)=CC=1.C(NCC)C>CCOCC>[N+:20](=[C:5]([C:4](=[O:10])[CH2:3][O:2][CH3:1])[C:6]([O:8][CH3:9])=[O:7])=[N-:21]
Reactant: COCC(=O)CC(=O)OC
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCOCC
Solvent: CCNCC
Product: COCC(=O)C(=[N+]=[N-])C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
Methyl 4-methoxy-3-oxobutanoate (4.28 g, 0.029 mol) was dissolved in ether (20 mL). The solution was cooled in an ice bath. To the solution was added p-toluenesulfonyl azide (5.78 g, 0.029 mol) followed by N-ethylethanamine (2.0 mL, 0.019 mol). The solution was stirred at 0° C. for 15 minutes, then at rt for 30 minutes. Upon evaporation, the tosyl amide bi-product solidified. This was filtered off and the filtrate was purified by flash chromatography to give the desired product (4.5 g, 89%) as a light oil. 1H NMR (400 MHz, CDCl3): δ 4.55 (s, 2H), 3.83 (s, 3H), 3.45 (s, 3H). MF═C6H8N2O4. LCMS calculated for C6H9N2O4 (M+H)+: m/z=173.0.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.Br[CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18].[Cl-].[NH4+].O1CCCC1>[Zn]>[CH3:18][C:17]([C:2]1([OH:1])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)([CH3:19])[CH:16]=[CH2:15]
Reactant: CC(C)=CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CC(C)(C)C1(O)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.62 h

Procedure:
To a suspension of tert-butyl 3-oxopyrrolidine-1-carboxylate (2.40 g, 0.0130 mol), 4-bromo-2-methyl-2-butene (3.00 mL, 0.0260 mol) in 15.0 mL sat'd. ammonium chloride and tetrahydrofuran (3.00 mL, 0.0370 mol) was added zinc (1.70 g, 0.0260 mol) at rt. Soon after stirring was started, gas and heat were released. After 30 to 45 min., the resulting light grey mixture was filtered through celite. The filtration was extracted with EtOAc. The organic layeres were combined, washed with brine, dried (NaSO4) and concentrated in-vacuo. The residue was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to give the desired product. LCMS (M+Na) 278.2.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:45])[CH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:45])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[C@H:10]([OH:11])[CH2:9][S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:18][CH:19]=2)=[CH:32][CH:31]=1)[CH3:26]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CSCc1ccccc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3[C@H](O)CSCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using (S)-2-benzylsulfanyl-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([SH:16])[C:14]=3[N:15]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=[CH:3]1.[CH3:23]I>[OH-].[Na+]>[CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([S:16][CH3:23])[C:14]=3[N:15]=2)=[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:4]=[CH:3]1
Reactant: CI
Reactant: Cn1cnc(-c2ccccc2)c1-c1nc2c(S)ncnc2s1
Agent: [Na+]
Agent: [OH-]
Product: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3C)nc12
Yield: 95 %

Procedure:
2-(1-Methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidine-7-thiol (Example 31) (2.91 g) was dissolved in 2M NaOH (50 mL) then methyl iodide (0.67 mL) added under an inert atmosphere at ambient temperature. After 2.5 hours the reaction mixture was filtered, washed with water, dried under high-vacuum to give the title compound as a pale brown solid (2.9 g, 95%);
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:17])[C:7]=2[C:6]([NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:5][CH:4]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O.[OH-].[Na+]>N1C=CC=CC=1>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][NH:18][C:6]1[C:7]2[C:8](=[O:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:15][C:16]=2[C:3]([CH2:2][NH:1][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:4][CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)CCNc1ccc(CN)c2sc3ccccc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CN(C)CCNc1ccc(CNS(C)(=O)=O)c2sc3ccccc3c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
4-(Aminomethyl)-1-[[2-(dimethylamino)ethyl]amino]-thioxanthen-9-one (2 g, 6 mmol) in 30 mL of dry pyridine under nitrogen was stirred at room temperature until the solution was complete. The solution was chilled in an ice-bath and 0.52 mL(6.7 mmol) of methanesulfonyl chloride in chilled pyridine was added dropwise and the mixture was stirred for 1 h at room temperature. The reaction mixture was poured into 500 mL of water containing 0.51 g of sodium hydroxide, extracted into chloroform, the organic layer was washed with water (2x) and brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo. The residue (2.5 g) was stirred in either, filtered, and dried to afford 2 g of N-[[1-[[2-(dimethylamino)ethyl]amino]-9-oxothioxanthen-4-yl]methyl]methane-sulfonamide, m.p. 126°-127° C. The free base was dissolved in MeOH and treated with methane sulfonic acid (0.48 g) to afford 2.0 g (67%) of the product as the methanesulfonate salt, m.p. 168° C. (dec.).
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[S:1][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Sc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCSc1ncccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
A mixture of 2-mercaptopyrimidine (7.3 g), N-(2-bromoethyl)phthalimide (16.5 g), potassium carbonate (10.8 g) and N,N-dimethylformamide (DMF) (85 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and the crystals separated were collected by filtration to obtain N-[2-(2-pyrimidinylthio)ethyl]-phthalimide (17.3 g, 93%). The resultant was recrystallized from ethanol-isopropyl ether to obtain pale yellow prisms, m.p. 149°-150° C.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][CH:4]([CH2:7][C:8]2[CH2:9][S:10][C@@H:11]3[C@H:31]([NH:32][C:33](=[O:81])/[C:34](=[N:60]\[O:61]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)/[C:35]4[N:36]=[C:37]([NH:40]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[S:38][CH:39]=4)[C:30](=[O:82])[N:12]3[C:13]=2[C:14]([O:16]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:15])[O:3]1>Cl.C(O)=O>[NH2:40][C:37]1[S:38][CH:39]=[C:35](/[C:34](=[N:60]/[OH:61])/[C:33]([NH:32][C@@H:31]2[C:30](=[O:82])[N:12]3[C:13]([C:14]([OH:16])=[O:15])=[C:8]([CH2:7][CH:4]4[O:3][C:2](=[O:1])[CH:6]=[CH:5]4)[CH2:9][S:10][C@H:11]23)=[O:81])[N:36]=1
Reactant: O=C1C=CC(CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)O1
Agent: Cl
Solvent: O=CO
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CC4C=CC(=O)O4)CS[C@H]23)cs1
Temperature: 25 °C
Yield: 23.7 %

Procedure:
Diphenylmethyl 3-(2,5-dihydro-2-oxofuran-5-ylmethyl)-7β-[2-(2-triphenylmethylaminothiazol-4-yl)-2-Z-triphenylmethoxyiminoacetamido]ceph-3-em-4-carboxylate, (0.375 g) was dissolved in a solution of 10% conc. hydrochloric acid in 98% formic acid (3 mls). Within a few minutes a colourless crystalline precipitate had formed. The solution was maintained at room temperature for 45 mins and then filtered. The solid was washed with a little 10% conc. hydrochloric acid/formic acid and then water. The solvent was removed from the filtrate in vacuo and the residue partitioned between water and ether (5 mls). The aqueous phase was adjusted to pH 3 and filtered. The yellow homogeneous solution was chromatographed on HP20SS, eluting with 2,4,6,8 and 10% THF/water (100ml portions). The fractions containing the product were combined, concentrated and freeze-dried to give the title compound as an amorphous white solid, (0.037 g, 24%), νmax (KBr) 1751 (v.broad), 1670, 1629, 1529, 1363, 1262 and 1178cm -1 ; 2.84 (1H, dd, J 4.6, 14.5Hz), 2.94 (1H, dd, J 7.5, 14.5Hz), 3.38 and 3.59 (2H, ABq, J 17.6Hz), 5.17 (1H, d, J 4.7Hz), 5.44 (1H, m), 5.73 (1H, d, J 4.7Hz), 6.16 (1H, dd, J 1.9, 5.8Hz), 7.06 (1H, s) and 7.70 (1H, dd, J 1.1, 5.8Hz); [mass spectrum: +ve ion (thioglycerol) MH+ 466, MNa+ 488].
Reaction SMILES: [Na].[CH:2]1[C:15]2[C:14](=[O:16])[C:13](=[N:17][OH:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Na+]>CC(C)=O>[C:19]([O:18][N:17]=[C:13]1[C:14](=[O:16])[C:15]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1C(=NO)c2ccccc2-c2ccccc21
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Product: O=C(ON=C1C(=O)c2ccccc2-c2ccccc21)c1ccccc1
Reaction time: 0.25 h

Procedure:
24.6 g (0.1 mole) of the sodium salt of 9,10-phenanthrene-dione-9-oxime are suspended in 100 ml of acetone, whereupon a solution of 15.4 g (0.11 mole) of benzoyl chloride and 50 ml of acetone is added under stirring. A slightly exothermic reaction takes place, sodium chloride is precipitated and within about an hour a dark brown solution is formed. The reaction having been completed, the reaction mixture is heated to boiling for 15 minutes and evaporated in vacuo. Thus 28.2 g of 9,10-phenanthrene-dione-9-benzoyl-oxime are obtained, yield, 86.2%, mp.: 148°-149° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[Cl:1][C:2]1[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: CC1COc2c(F)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: CC1COc2c(N3CCN(C)CC3)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Yield: 34.4 %

Procedure:
150 mg (0.5 mmol) of 9-chloro-10-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid was suspended in 3 ml of dimethyl sulfoxide and 150 mg of N-methylpiperazine was added to the suspension. The mixture was then allowed to react at 120°-130° C. (bath temperature) for 6 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was washed with diethyl ether to remove any insoluble substance. The resulting residue was purified by silica gel (7 g) column chromatography using methanol-chloroform (5:95 by volume) and then methanol-chloroform (10:90 by volume) as eluants, and the resulting product was recrystallized from ethanol to provide 65 mg (34.4% yield) of 9-chloro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid as pale yellow fine needles with m.p. 275°-276° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:10])=[CH:4][C:5](=O)[O:6][C:7]=1[CH3:8].[NH3:11]>O1CCOCC1>[CH3:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([OH:6])=[N:11][C:7]=1[CH3:8]
Reactant: Cc1oc(=O)cc(O)c1C
Reactant: N
Solvent: C1COCCO1
Product: Cc1nc(O)cc(O)c1C
Temperature: 25 °C

Procedure:
5,6-Dimethyl-4-hydroxy-2-oxo-2H-pyran (J. Chem. Soc. Perkin Trans 1, 1980, 2272) (10 g, 71 mmol) was dissolved in 66 mL of dioxan and 33 mL of 0.88 NH3 solution and the mixture refluxed for 3 h. The resulting suspension was then allowed to cool to room temperature overnight, filtered and the solid collected and dried in vacuo to provide the title compound as a white crystalline solid (6.5 g). The filtrate was concentrated to approximately 10 mL in vacuo, and a second crop of solid collected by filtration (1.0 g). Both crops were combined and used in the next synthetic step.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[CH:14][N:13]=[C:12]([N:25]([CH3:27])[CH3:26])[N:11]=2)=[CH:5][CH:4]=1.[NH3:28]>O1CCOCC1>[NH2:28][C:18]1[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([C:15]2[C:10]([NH:9][C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:11][C:12]([N:25]([CH3:27])[CH3:26])=[N:13][CH:14]=2)[N:17]=1
Reactant: N
Reactant: COc1ccc(Nc2nc(N(C)C)ncc2-c2nc(C)nc(SC)n2)cn1
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N(C)C)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 73.8 %

Procedure:
A glass microwave reaction vessel was charged with N4-(6-methoxypyridin-3-yl)-N2,N2-dimethyl-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidine-2,4-diamine (16 mg, 0.042 mmol), ammonia (0.5 mL, 23.11 mmol) (30% in water) and dioxane (1 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 5% MeOH/EtOAc to give 5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-N4-(6-methoxypyridin-3-yl)-N2,N2-dimethylpyrimidine-2,4-diamine (11 mg, 0.031 mmol, 74.8% yield). 1H NMR (300 MHz, CDCl3) δ 11.94 (s, 1H); 9.29 (s, 1H); 8.42 (s, 1H); 8.07 (dd, J=8.92, 2.34 Hz, 1H); 6.76 (d, J=8.77 Hz, 1H); 5.29 (s, 2H); 3.95 (s, 3H); 3.23 (s, 6H); 2.48 (s, 3H). m/z (ESI, +ve ion) 354.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1C=CC=CC=1)=[O:5].[CH:18]([C:21]1[N:22]=[C:23]([C:26](O)=[O:27])[S:24][CH:25]=1)(C)C.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:4]([C:3]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:2]=1[NH:1][C:26]([C:23]1[S:24][CH:25]=[C:21]([CH3:18])[N:22]=1)=[O:27])(=[O:5])[CH3:6]
Reactant: COc1ccc(C(=O)c2ccccc2)c(N)c1
Reactant: CC(C)c1csc(C(=O)O)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C)cs2)c1
Temperature: -30 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
Step E) To a suspension of 2.59 g (15.7 mmol) of 2-amino-4-methoxybenzophenone (product of step D) and 2.68 g (15.7 mmol) of 4-isopropylthiazole-2-carboxylic acid (product of step C) in 75 mL of pyridine cooled to −30° C., was added 1.93 mL (23.5 mmol) of POCl3 slowly dropwise over 5 min. The mixture was stirred 3 h, warmed to room temperature and was stirred overnite. The reaction mixture was poured into ice water, and extracted several times with EtOAc. The combined EtOAc extracts were dried (MgSO4), concentrated and chromatographed over SiO2 (eluted with 0% to 15% MeOH/EtOAc) to afford 2.57 g (51%) of 4-Methylthiazole-2-carboxylic acid (2-acetyl-5-methoxyphenyl)amide as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 1.41 (d, J=6.7 Hz, 6H), 2.64 (s, 3H), 3.24 (m, 1H), 3.91 (s, 3H), 6.67 (dd, J=9, 2.5 Hz, 1H), 7.18 (s, 1H), 7.86 (d, J=9 Hz, 1H), 8.56 (d, J=2.5 Hz, 1H), 13.48 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([C:15]([CH3:17])=O)[C:10](OCC)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]([NH2:21])=[S:20].[O-]CC.[Na+].[Na]>C(O)C>[C:1]1([CH2:7][CH2:8][C:9]2[C:10](=[O:11])[NH:18][C:19](=[S:20])[NH:21][C:15]=2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(CCc1ccccc1)C(C)=O
Reactant: NC(N)=S
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1[nH]c(=S)[nH]c(=O)c1CCc1ccccc1

Procedure:
Ethyl α-(phenylethyl)acetoacetate (23.4 g) and thiourea (10.65 g) were added to a solution of sodium ethoxide in ethanol (100 ml) prepared from sodium (4.6 g). The mixture was refluxed for 51/2 hours and evaporated to dryness. The solid residue was dissolved in water and acetic acid was added to pH 4. The white precipitate was filtered off and recrystallised from ethanol to give 5-(2-phenylethyl)-6-methyl-2-thiouracil m.p. 210°-214°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[C:8]([CH2:14][OH:15])[CH:7]=1.[CH3:16][C:17]([S:24][S:25][CH3:26])([CH3:23])[CH2:18][CH2:19][C:20](O)=[O:21].C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:16][C:17]([S:24][S:25][CH3:26])([CH3:23])[CH2:18][CH2:19][C:20]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[C:8]([CH2:14][OH:15])[CH:7]=1)=[O:21]
Reactant: CSSC(C)(C)CCC(=O)O
Reactant: NCCCOc1cc(CO)cc(CO)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CSSC(C)(C)CCC(=O)NCCCOc1cc(CO)cc(CO)c1
Reaction time: 15 h
Yield: 54.7 %

Procedure:
To a solution of 1-(3-amino-propyloxy)-3,5-bis-(hydroxymethyl)-benzene (50 mg) in dimethylformamide (1 mL) was added 4-methyl-4-methyldisulfanyl-pentanoic acid (44 mg), N,N′-diisopropylcarbodiimide (35 mL) and 1-hydroxybenzotriazole hydrate (5.8 mg). After 15 h at room temperature, water was added to the reaction mixture and the aqueous solution was extracted twice with ethyl acetate. The combined organic solutions were washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated in vacuo to a residue. The residue was purified by silica gel chromatography (Interchrom Puriflash 5 g column, SiOH 15-35 μm), eluted with methanol/dichloromethane, 5:95 to give 1-[3-(4-methyl-4-methyldisulfanyl-pentanoylamino)-propyloxy]-3,5-bis-(hydroxymethyl)-benzene (48 mg):
Reaction SMILES: [C:1]12([CH3:43])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=[C:10]=[C:11]1[CH:42]=[CH:41][C:14]([NH:15][C:16]2[N:21]=[C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26](=[C:29]=[C:30]4[CH2:35][CH:34]5[C:36]([CH3:38])([CH3:37])[C:31]4([CH3:39])[CH2:32][CH2:33]5)[CH2:25][CH:24]=3)[N:19]=[C:18](Cl)[N:17]=2)=[CH:13][CH2:12]1.[CH2:44]([O-:46])[CH3:45].[Na+]>>[C:1]12([CH3:43])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=[C:10]=[C:11]1[CH:42]=[CH:41][C:14]([NH:15][C:16]2[N:21]=[C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26](=[C:29]=[C:30]4[CH2:35][CH:34]5[C:36]([CH3:38])([CH3:37])[C:31]4([CH3:39])[CH2:32][CH2:33]5)[CH2:25][CH:24]=3)[N:19]=[C:18]([O:46][CH2:44][CH3:45])[N:17]=2)=[CH:13][CH2:12]1
Reactant: CC[O-]
Reactant: CC12CCC(CC1=C=C1C=CC(Nc3nc(Cl)nc(NC4=CCC(=C=C5CC6CCC5(C)C6(C)C)C=C4)n3)=CC1)C2(C)C
Agent: [Na+]
Product: CCOc1nc(NC2=CCC(=C=C3CC4CCC3(C)C4(C)C)C=C2)nc(NC2=CCC(=C=C3CC4CCC3(C)C4(C)C)C=C2)n1

Procedure:
2,4-Bis(4-camphylidenemethylene-anilino)-6-chloro-1,3,5-triazine is reacted with sodium ethanolate analogously to the instructions of Example 2. The desired product forms to the extent of 43%.
Reaction SMILES: O1CCCCC1[O:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]([N+:22]([O-])=O)=[CH:20][N:19](C3CCCCO3)[N:18]=2)=[O:16])[CH2:10][CH2:9]1>CO.[Pd]>[OH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]([NH2:22])=[CH:20][NH:19][N:18]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: O=C(NC1CCC(OC2CCCCO2)CC1)c1nn(C2CCCCO2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1c[nH]nc1C(=O)NC1CCC(O)CC1
Yield: 165.8 %

Procedure:
A solution of 4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylic acid [4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amide (0.3 g; 0.71 mmol) in methanol (25 ml), was treated with 10% palladium on carbon (30 mg) then hydrogenated at room temperature and pressure overnight. The catalyst was removed by filtration and washed three times with methanol. The filtrate was evaporated to give 0.264 g of the required product. (LC/MS: Rt 2.39, [M+H]+ 393).
Reaction SMILES: C[C:2](C1C=CC(O)=CC=1)([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=CC=1)C.C=O.[NH2:20][CH2:21][CH2:22][CH2:23][Si](OCC)(OCC)OCC>C(Cl)(Cl)Cl>[O:10]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:2][C:23]=2[CH:22]=[CH:21][NH:20]1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: C=O
Solvent: ClC(Cl)Cl
Product: C1=Cc2ccccc2ON1
Yield: 75 %

Procedure:
In FIG. 6A, BPA (10 g, 43.8 mmol), methanal (5.26 g, 175 mmol) and 3-aminopropyl-triethoxysilane (19.4 g, 87.6 mmol) are mixed in chloroform (100 mL) for reaction at 85 Celsius degrees (° C.) for 24 hours (hr). The product obtained after the reaction do not need to be further purified. The product is directly condensed to obtain an anticipated product Bz-BES (yield: 75%). Elemental analysis calcd (%) for C37H62N2O8Si2: C 61.83, H 9.63, N 3.89; found C 61.70, H 8.67, N 3.81.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[Li+].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.CI>CN(C=O)C>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][CH2:6][N:7]([CH3:22])[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(CCNC(=O)OCc1ccccc1)OCC
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(CCN(C)C(=O)OCc1ccccc1)OCC
Reaction time: 0.08 h

Procedure:
A solution of phenylmethyl [3,3-bis(ethyloxy)propyl]carbamate (4.17 g, 14.8 mmol, J. Med. Chem. 1998 41, 3919-3922) in anhydrous DMF (15 mL) under nitrogen at ambient temperature was treated LiHMDS (1.0 M in THF, 17.8 mL, 17.8 mmol). After stirring 5 min., methyl iodide (1.11 mL, 17.8 mmol) was added. After stirring an additional 15 min., the reaction mixture was quenched by addition of saturated brine, water and Et2O. After separation of the phases, the aqueous layer was back-extracted with Et2O. The combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered, evaporated in vacuo and purified on silica gel eluting with 25% EtOAc in Hexanes to provide the product as an oil: 1H NMR (CDCl3) δ 7.28-7.38 (5H, m), 5.12 (2H, s), 4.45-4.56 (1H, m), 3.29-3.68 (6H, m), 2.92 (3H, s), 1.81-1.90 (2H, m), 1.11-1.23 (6H, m); ES+ MS: 318 (M+Na+).