Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([C:49]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[O:50])[CH:45]=[CH:46][C:47]=1[CH3:48].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([C:49]([N:51]6[CH2:52][CH2:53][O:54][CH2:55][CH2:56]6)=[O:50])[CH:45]=[CH:46][C:47]=5[CH3:48])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1ccc(C(=O)N2CCOCC2)cc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(C(=O)N4CCOCC4)ccc3C)cn2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A solution of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg, 0.093 mmol), (3-bromo-4-methyl-phenyl)-morpholin-4-yl-methanone (68 mg, 0.232 mmol) obtained in Step A, Pd2dba3 (8.5 mg, 0.0093 mmol), S-Phos (7.6 mg, 0.0186 mmol) and potassium phosphate (39 mg, 0.186 mmol) in dimethylformamide (1 ml) was degassed under ultrasonic irradiation, followed by stirring at 100° C. for 4 hours. After the reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, followed by extraction twice with ethyl acetate (10 ml). The organic layer was washed with brine (10 ml), and dried over sodium sulfate, followed by distilling off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1), whereby [3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methyl-phenyl]-morpholin-4-yl-methanone was obtained as a brown oil (70 mg, 100%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Br[CH2:7][C:8]1[CH:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].[Cl-].[NH4+]>CS(C)=O>[C:1]([O:4][CH2:7][C:8]1[CH:17]=[CH:16][C:15]([CH2:18][O:4][C:1](=[O:3])[CH3:2])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(CBr)ccc1CBr
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(COC(C)=O)ccc1COC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
Sodium acetate (10.4 g, 126.8 mmol) was added to a solution of methyl 2,5-bis(bromomethyl)benzoate (described in J. Am. Chem. Soc., 121, 1192 (1999); 12.65 g, 39.3 mmol) in dimethyl sulfoxide (80 ml), and the mixture was stirred at room temperature for 1 hour. After a saturated aqueous solution of ammonium chloride (150 ml) was added thereto, the product was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure. The obtained oily residue was subjected to chromatography on a silica gel (200 g) column (eluent; ethyl acetate:hexane=1:5˜1:2) to afford the title compound (7.72 g, 70% yield) as an oil.
Reaction SMILES: [C:1](=[O:16])([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Rh].CC(O)C>[CH:3]1([NH:2][C:1](=[O:16])[O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=C(Nc1ccccc1)OC1CCCCC1
Agent: [Rh]
Solvent: CC(C)O
Product: O=C(NC1CCCCC1)OC1CCCCC1
Reaction time: 0.4 h
Yield: 97 %

Procedure:
A mixture of 21.9 g. (0.10 mole) of cyclohexyl carbanilate, 100 ml. of 2-propanol, and 2.4 g. of 5% Rh on carbon was added to a 300-ml. Magne Drive autoclave. The vessel was sealed, purged first with nitrogen and then with hydrogen, and pressured with hydrogen to 700 psig. The autoclave was agitated at 25° and 500-800 psig for 0.4 hr., followed by an additional 0.9 hr. with little or no gas absorption. The autoclave was cooled and depressurized. The reaction product was removed and filtered through Celite filter aid to remove the catalyst. The solvent was removed in a rotary evaporator under vacuum. The white solid residue consisted of 21.9 g. (97% yield) of cyclohexyl cyclohexylcarbamate, m.p. 77°-78°.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[N+:11]([C:14]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:25][O:24][CH2:23]2)[CH:18]=[CH:17][C:15]=1[NH2:16])([O-:13])=[O:12]>>[N+:11]([C:14]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:23][O:24][CH2:25]2)[CH:18]=[CH:17][C:15]=1[NH:16][CH:8]=[O:10])([O-:13])=[O:12]
Reactant: Nc1ccc(OC2COC2)cc1[N+](=O)[O-]
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Product: O=CNc1ccc(OC2COC2)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 50.6 %

Procedure:
A stirred mixture of acetic anhydride (15 mL, 161 mmol) and formic acid (6 mL, 161 mmol) was heated at 60° C. for 5 h. The mixture was cooled to rt, then 2-nitro-4-(oxetan-3-yloxy)aniline (1.69 g, 8.02 mmol) was added and the mixture was heated at 70° C. for 15 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aq NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 20% EtOAc in hexanes to 100% EtOAc to afford N-(2-nitro-4-(oxetan-3-yloxy)phenyl)formamide (967 mg, 51%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 10.36 (br s, 1H), 8.29 (m, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.36 (d, J=1.8 Hz, 1H), 7.24 (dd, J=9.0, 3.0 Hz, 1H), 5.38 (pentet, J=4.9 Hz, 1H), 4.92-4.94 (m, 2H), 4.53-4.56 (m, 2H).
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: O=C(Nc1cccc(Br)c1)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1cccc(Br)c1)Oc1ccc2c(c1)CCCN2

Procedure:
A nitrogen flushed mixture of 3-bromo-phenyl -carbamic acid 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-yl ester (0.218 g., ½ mmol) and 5% Pd—C (0.02 g.) in absolute ethanol (25 ml) was shaken in a par apparatus at room temperature (38° C.) under 50 psi pressure of hydrogen for 4 hours. Pd—C was then discarded through filtration. The reaction mixture was concentrated under reduced pressure and the residue was washed with dichloromethane (2×3 ml) to give 2c; yield: 0.16 g. (92.4%), m.p.: 198° C., C16H15BrN2O2, 1H NMR δ ppm (CDCl3+DMSO-d6): 1.73-1.81 (m, 2H), 2.55 (t, 2H), 3.06 (t, 2H), 6.67-6.98 (m, 4H), 6.90-7.20 (m, 2H), 7.36 (bs, 1H), 9.39 (bs, 1H), IR vmax (KBr) (cm−1): 509, 694, 758, 815, 886, 1012, 1084, 1149, 1216, 1319, 1352, 1442, 1504, 1549, 1600, 1710, 2365, 2479, 2727, 2827, 2927, 3420, 3780.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:22]([OH:25])(=[O:24])=[O:23])[C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)([O-])=O.[S-2].[Na+].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([S:22]([OH:25])(=[O:23])=[O:24])[C:7]([CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:16][CH:17]=2)=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1ccc(C=Cc2ccc([N+](=O)[O-])cc2S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Product: CC(=O)Nc1ccc(C=Cc2ccc(N)cc2S(=O)(=O)O)cc1

Procedure:
If the nitro group of the 4-nitro-4'-acetylaminostilbene-2-sulphonic acid obtained according to a) is reduced in aqueous ethanol with sodium sulphide or analogously to the procedure in DOS (German Patent Specification) 3,805,513, Example 3, 4-amino-4'-acetylaminostilbene-2-sulphonic acid is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C(O)CCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCCCCCOc1ccc(F)cc1
Yield: 106.4 %

Procedure:
12-Bromododecanoic acid (1 g) was stirred in 10% hydrochloric acid-methanol for 4 hours. The mixture was then concentrated and distributed into chloroform and water, and the chloroform layer was dried with anhydrous sodium sulfate to give the methyl ester of 12-bromoundecanoic acid (1.01 g). To para-fluorophenol (0.38 g) dissolved in dimethylformamide (DMF) was added 60% NaH (0.40 g), and the mixture was stirred. To this mixture was added 12-bromododecanoic acid (1 g), and the mixture was stirred for 12 hours. The reaction mixture, after having been concentrated and adjusted to a weak acidic range of pH by adding citric acid, was extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated to give 12-para-fluorophenoxydodecanoic acid (1.12 g). The product was dissolved in a mixed solvent of ethanol-water (1:1), and potassium hydroxide (0.6 g) was added to the solution. The mixture was stirred at 80° C. for 30 minutes. The reaction mixture was diluted with water (80 ml), adjusted to acidic range of pH by adding citric acid, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give 12-para-fluorophenoxy-dodecanoic acid (1.03 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([SH:16])=[N:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.I[C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[CH:19]=1.N1C=CC=CC=1C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu]I.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([S:16][C:18]4[CH:26]=[CH:25][C:24]5[C:20](=[CH:21][N:22]([CH3:27])[N:23]=5)[CH:19]=4)=[N:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc2cc(I)ccc2n1
Reactant: Cn1cc(-c2ccc3nnc(S)n3n2)cn1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5nn(C)cc5c4)n3n2)cn1
Temperature: 100 °C
Reaction time: 10 h
Yield: 87.2 %

Procedure:
To a solution of 6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (50 g, 268 mmol) in DMF (750 mL) is added 5-iodo-2-methyl-2H-indazole (55.5 g, 215.1 mmol), 2-Pyridinecarboxylic Acid (5.5 g, 44.7 mmoles), Copper (I) Iodide (4 g, 21.0 mmoles), and Cesium Carbonate (212.5 g, 652.2 moles). The mixture is under N2 and stirred at 100° C. for 10 hours. The reaction mixture is then cooled to room temperature and poured into water (2000 mL). After stirring at room temperature for 30 min, the mixture is extracted with a mixed solvent (2 L×2, CHCl3/IPA=3/1). The combined organic layer is then washed four times with mixed solution (25% NH4OH(aq)/brine=¼; 800 mL), sat. LiCl(aq) (1 L), sat. brine (1.5 L×2), and dry over Na2SO4. The organic solution is concentrated under reduced pressure to give a brown crude solid product. The crude product is triturated with ethyl acetate (800 mL) at room temperature for 3 hours and the pure product is collected by filtration to afford the title compound (68 g, 87.2%) as a white solid. MS (m/z): 363.0 (M+H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)=[O:9].CN([CH:22]=[O:23])C>>[CH:22]([C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([C:8]([O:7][CH3:6])=[O:9])[CH:11]=2)[NH:15][CH:14]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2[nH]cc(C=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Place anhydrous DMF (25 mL) in a flask under an atmosphere of nitrogen, cool to 10° C. and treat dropwise with POCl3 (8.22 g, 54 mmol) while keeping the temperature below 15° C. Add a solution of 5-methoxycarbonyl-1H-indole in 30 mL DMF portionwise keeping the temperature below 20° C. Remove the cooling bath and stir the mixture at ambient temperature for 1 hour then pour onto ice. Addition of 50 mL 5N NaOH precipitated a solid which is filtered and rinsed with water and EtOAc to give the title compound: 1H NMR (DMSO-d6) 9.95 (s, 1H), 8.76 (s, 1H), 8.4 (s, 1H), 7.9–7.8 (m, 1H), 7.5–7.7 (d, 1H), 3.85 (s, 3H), 1.7 (s, 1H); ISMS 204 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:20](=[CH:21][CH:22]=1)[O:19][C:7]1[C:8]([F:18])=[N:9][C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][C:6]=1[C:5]2=O.[CH3:24][Si](C[Li])(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:20](=[CH:21][CH:22]=1)[O:19][C:7]1[C:8]([F:18])=[N:9][C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][C:6]=1[C:5]2=[CH2:24]
Reactant: [Li]C[Si](C)(C)C
Reactant: CC(C)(C)COc1cc2c(=O)c3cc(Br)ccc3oc2c(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C=C1c2cc(Br)ccc2Oc2c1cc(OCC(C)(C)C)nc2F
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a suspension of 7-bromo-1-fluoro-3-(neopentyloxy)-5H-chromeno[2,3-c]pyridin-5-one (1000 mg, 2.63 mmol) in THF (25 mL) at −40° C. was added drop wise ((trimethylsilyl)methyl)lithium (1.0M solution in pentane; 3.95 mL, 3.95 mmol). After 10 min, TFA (0.304 mL, 3.95 mmol) was added drop wise and the reaction mixture was allowed to warm to rt Additional 1 ml of TFA was added and the reaction mixture was allowed to stir for 1 hour at P. An aqueous, saturated K2CO3 solution was added, followed by EtOAc. The organic phase was separated and dried over Na2SO4. The solvent was removed under reduced pressure to yield 7-bromo-1-fluoro-5-methylene-3-(neopentyloxy)-5H-chromeno[2,3-c]pyridine as a yellow solid (995 mg), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)(O)[O-:23].[K+].C=O.Cl>C(#N)C>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH2:22][OH:23])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CCOC(=O)C(CCOCc1ccccc1)C(=O)OCC
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(CO)(CCOCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
2.85 g (9.67 mmol equivalents) of diethyl 2-(2-benzyloxyethyl)malonate was dissolved in 20 mL of acetonitrile, 1.60 g (11.7 mmol equivalents) of potassium bicarbonate and 465 mg (11.7 mmol equivalents as formaldehyde) of paraformaldehyde were added thereto, and the mixture was stirred at room temperature (25° C.) overnight. After completion of the reaction, a 0.5 mol/L aqueous solution of hydrochloric acid was added dropwise to the reaction liquid, and the mixture was extracted three times with chloroform. The combined chloroform layers were dried with anhydrous magnesium sulfate and then concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=4/1) to give 2.78 g (8.76 mmol equivalents) of diethyl 2-(2-benzyloxyethyl)-2-hydroxymethylmalonate.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:20][C@@H:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][C@H:7]1[C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5])[CH3:3].[H][H]>[Pd]>[NH2:1][C@H:2]([C:4]([N:6]1[CH2:20][C@@H:19]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:18][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3]
Reactant: C[C@H](N)C(=O)N1C[C@@H](Cc2ccccc2)C[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: C[C@H](N)C(=O)N1C[C@@H](Cc2ccccc2)C[C@H]1C(=O)O

Procedure:
A solution of 10 grams of 1-(L-alanyl)-4-(S)-(phenylmethyl)-L-proline, phenylmethyl ester (liberated from its hydrochloride salt) in 150 ml. of absolute alcohol is hydrogenated in the presence of 1.5 grams of 10% palladium on carbon until the uptake of hydrogen ceases. The mixture is filtered to remove the catalyst and the filtrate is concentrated under reduced pressure to yield the desired 1-(L-alanyl)-4-(S)-(phenylmethyl)-L-proline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([OH:10])[CH3:9]
Reactant: COC(=O)CCCCC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCC(C)O
Reaction time: 0.5 h

Procedure:
Put 10 g (63.2 mmol) 6-oxo-heptanoic acid methyl ester in 50 ml methanol. Add, in portions, 1.196 g (31.6 mmol) sodium borohydride. After the exothermic reaction has subsided, stir for a further 30 min under reflux. Then concentrate by evaporation. Take up the residue in water, acidify with 1 M hydrochloric acid and extract twice with dichloromethane. Dry the organic phases and concentrate by evaporation. 7.9 g (78.0% of theor.) of the target compound is obtained.
Reaction SMILES: O=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[NH:11]1[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]1=[O:13]>N1C=CC=CC=1>[CH:17]1[C:15]([NH2:16])=[N:14][C:12](=[O:13])[N:11]([C@@H:2]2[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]2[OH:4])[CH:18]=1
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Nc1cc[nH]c(=O)n1
Solvent: c1ccncc1
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
M-PEOZ-O—CH2—CO2—NHS (M-PEOZ-SCM 5000) (180 mg, 0.034 mmol) was dissolved in 11 mL of pyridine and added to a solution of cytosine arabinose (Ara-C) (5.7 mg, 0.023 mmol), previously dissolved in 5 mL of anhydrous pyridine at 0° C. The resulting solution stirred for 72 hours at room temperature. Reverse phase HPLC (C-18 column) showed that reaction was complete. After evaporation of the solvent, the product was dissolved in methylene chloride (5 mL) and added drop by drop into 150 mL ether. The precipitate was collected by centrifugation at 4° C. and dried under vacuum. Yield 150 mg, 80%. NMR showed the usual peaks of the M-PEOZ backbone (above) plus the pyrimidine protons of Ara-C at 7.31, 7.67, 8.16, and 8.62 ppm. Exposure of the conjugate to pH 8 buffer showed that Ara-C is slowly released (15% after 24 hours), so the conjugate can be regarded as a prodrug.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[O:14]=[CH:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:15]([OH:14])[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)NCCC=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCC(O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
A solution of 2,5-dibromopyridine (5 g, 21 mmol), in dry toluene (200 mL, 0.1 M) is cooled to −75° C. under a blanket of nitrogen. 2.5 M n-BuLi in hexanes (16 mL, 25 mmol, 1.2 eq) is added drop-wise maintaining a temp less than −73° C. and the reaction mixture is stirred at −73° C. to −78° C. for 2 hours. The mixture is then added to a solution of tert-butyl (3-oxopropyl)carbamate (3.66 g, 21 mmol) in toluene (50 mL) at −78° C. The reaction mixture is stirred at −78° C. for 1 hour, before being allowed to warm slowly to room temperature and stirred overnight. The reaction mixture is quenched with saturated ammonium chloride solution (100 ml) and the toluene phase is separated and concentrated. The crude material is purified by chromatography (0-45% ethyl acetate in heptane) to give the title compound (3.1 g). MS (ESI+) m/z 331.0 [M+H].
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[C:11]([F:15])[CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([CH3:16])[C:5]=2[N:4]=[CH:3]1.[OH:17]O>>[CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[C:11]([F:15])[CH:10]=[CH:9][C:8]=3[N+:7]([O-:17])=[C:6]([CH3:16])[C:5]=2[N:4]=[CH:3]1
Reactant: Cc1nc2ccc(F)cc2c2c1ncn2C
Reactant: OO
Product: Cc1c2ncn(C)c2c2cc(F)ccc2[n+]1[O-]

Procedure:
Using the method of Example 74, 1,4-dimethyl-8-fluoro-1H-imidazo[4,5-c]quinoline (from Example 140) was reacted with hydrogen peroxide to provide 1,4-dimethyl-8-fluoro-1H-imidazo[4,5-c]quinolin-5-oxide, m.p. 245°-248° C. Analysis: Calculated for C12H10FN3O: %C, 62.3; %H, 4.4; %N, 18.2; Found: %C, 62.7; %H, 4.3; %N, 18.3.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])[C:5]2[CH:28]=[CH:29][NH:30][C:4]=2[C:3]1=[O:31].CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2C=CC=CC=2)C2C=CNC=2C1=O>>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:26])([F:27])[F:25])=[C:8]([C:6]2[C:5]3[CH:28]=[CH:29][NH:30][C:4]=3[C:3](=[O:31])[N:2]([CH3:1])[CH:7]=2)[CH:13]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2C(F)(F)F)c2cc[nH]c2c1=O
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Product: Cn1cc(-c2cc(N)ccc2Oc2ccccc2C(F)(F)F)c2cc[nH]c2c1=O

Procedure:
Example 32b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 32a for the product of Example 2b, to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:24][NH2:25])=[C:4]([C:16]2C=C(Cl)C=CC=2Cl)[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1.C[C:27]1[CH:31]=[CH:30][S:29][C:28]=1C=C(C#N)C#N>>[NH2:1][C:2]1[C:3]([CH2:24][NH2:25])=[C:4]([C:16]2[S:29][CH:28]=[CH:27][C:31]=2[CH3:30])[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1
Reactant: Cc1ccsc1C=C(C#N)C#N
Reactant: Cn1c(=O)c2c(-c3cc(Cl)ccc3Cl)c(CN)c(N)nc2n(C)c1=O
Product: Cc1ccsc1-c1c(CN)c(N)nc2c1c(=O)n(C)c(=O)n2C
Yield: 17.1 %

Procedure:
The title compound was prepared using the procedures described in the preparation of Compound 8 (Example 7). The only difference was that after the synthesis of 2-(3-methyl-thiophen-2-ylmethylene)-malononitrile, the reaction was carried onto the next step without further work-up or purification, and propanol was used instead of ethanol. Furthermore, after the hydrogenation using BH3.THF, the reaction mixture was concentrated. An ample amount of MeOH was added until there was no more bubbling. The mixture was dried in vacuo, and purified by prep. HPLC. After washing the product with EtOAc, an amount of 82.4 mg (17.1% yield) of the title compound was collected. 1H NMR (400 MHz, d6-DMSO): δ ppm 7.80 (br s, 3H), 7.53 (d, J=4.0 Hz, 1H), 7.36 (br s, 2H), 6.96 (d, J=4.0 Hz, 1H), 3.80 (m, 2H), 3.51 (s, 3H), 3.10 (s, 3H). MS [m+H] calc'd for C15H17N5O2S, 332.0, 333.2. found 332.0, 333.2.