Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]([CH3:20])[CH:6]=1)(=O)C.[O-]CC.[Na+].Cl>C(O)C>[OH:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]([CH3:20])[CH:6]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OC(C)=O)cc1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Temperature: 50 °C

Procedure:
A solution of ethyl 2-[4-(acetyloxy)-2-methylphenoxy]-2-methylpropanoate (intermediate 9, 40.8 g) in ethanol (280 ml) was treated with sodium ethoxide (12.9 g) at room temperature under nitrogen. The resulting solution was heated to 50° C. for 1 hour. 2M hydrochloric acid (95 ml) was added to the cooled reaction and the solution concentrated. The residue was dissolved in t-butylmethyl ether and the resulting solution washed with water followed by brine and then dried over sodium sulfate, filtered and the filtrate concentrated to give a brown oil. Further purification by Biotage® chromatography eluting initially with cyclohexane and then cyclohexane:ethyl acetate (5:1) gave the title compound as an orange oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:22][CH2:23][CH:24]([CH2:27][O:28][C:29]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:25][OH:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>N1C=CC=CC=1>[CH2:6]([O:22][CH2:23][CH:24]([CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:27][O:28][C:29]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCOCC(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COS(C)(=O)=O
Temperature: 0 °C
Yield: 99.3 %

Procedure:
Methanesulfonylchloride (0.752 g, 6.57 mmol) was added to a solution of 4 (3.00 g, 5.26 mmol) in dry pyridine (15 ml). After 3 hours the solution was poured into ice water and the product was extracted 3 times with hexane. The hexane extracts were washed with cold 1M H saturated NaHCO3 and water, and dried over Na2SO4 and concentrated. Chromatography on silica gel using hexane-CH2Cl2 (1:1 v/v) afforded 3.40 g (99%) the title compound (9) as a waxy solid, m.p. 39°. NMR (CDCl3, (CH3)4Si); δ0.90 (t, 3H, J=6 Hz, --CH3), 1.25 (s, 26H, --CH2 --), 1.52 (m, 2H, OCH2CH2R), 2.28 (m, 1H, CH), 2.84 (s, 3H, --CH3), 3.19, 3.21 (ABX, 2H, JAB = 10 Hz, /JAX +JBX /=8 Hz, CH2OTr, 3.35 (t, 2H, J=6.5 Hz, --OCH2R), 3.48 (d, 2H, J=6 Hz, CH2OR), 4.39 (d, 2H, J=6 Hz, CH2OMs).
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:37]([CH3:39])[CH3:38])[CH:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1>O1CCCC1.C(O)C.[Pd]>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:37]([CH3:39])[CH3:38])[CH:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:31])[CH3:32])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 12 h
Yield: 88.5 %

Procedure:
To a solution of 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (12.4 g) in tetrahydrofuran (100 mL) and ethanol (60 mL) was added 10% (w/w) palladium on carbon (1 g) and the suspension was placed under a hydrogen atmosphere (3.4 bar) and shaken for 12 h. The solution was filtered through diatomaceous earth to give an oil which crystallized from ether to provide 2-(5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide as a white solid (8.7 g); MS: m/z=513(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[OH:16][C@H:15]([CH2:17][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: C1CCNC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H]1CO1
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H](O)CN1CCCC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A mixture of the (2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (250 mg, 0.66 mmol), (prepared as described for the starting material in Example 269), and pyrrolidine (1.5 ml) in THF (10 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatography using gradient elution with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to give (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (165 mg, 55%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:17]([N:18]=[N+:19]=[N-:20])[C@@H:16]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[O:14][C@H:6]1SC1C=CC=CC=1)(=[O:3])[CH3:2].[Br:30]Br.CCCCCCC.C1CCCC=1>C(Cl)Cl.CCOC(C)=O>[C:1]([O:4][C@@H:5]1[C@@H:17]([N:18]=[N+:19]=[N-:20])[C@@H:16]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[O:14][C@@H:6]1[Br:30])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](OC(C)=O)[C@@H](N=[N+]=[N-])[C@H]1OC(C)=O
Reactant: BrBr
Agent: C1=CCCC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](N=[N+]=[N-])[C@H]1OC(C)=O

Procedure:
Compound 7 (237.4 mg, 560 μmol) was dissolved in dry CH2Cl2 (2 mL), and bromine (32 μl, 620 μmol) was added. The reaction was monitored by TLC (heptane:EtOAc, 1:1). When the reaction was complete, a small amount of cyclopentene was added to the reaction mixture to remove the rests of Br2. The mixture was concentrated under reduced pressure and purified by quick Flash chromatography (Eluyent: 500 mL heptane:EtOAc, 2:1).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[O:11][C:12]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C(OC)=O)[C:13]=3[C:14]=2[CH3:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]1([NH:7][C:8]([C:10]2[O:11][C:12]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[C:13]=3[C:14]=2[CH3:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Oc1cccc2oc(C(=O)Nc3ccccc3)c(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1c(C(=O)Nc2ccccc2)oc2cccc(O)c12
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A mixture of N-phenyl-4-methoxycarbonyloxy-3-methylbenzofuran-2-carboxamide (328 mg, 1 mmole), methanol (1.5 m) and 10% potassium carbonate solution (1.5 ml) was stirred under argon overnight. After partial neutralization with acetic acid (0.06 ml) and evaporation to about 5 ml, water and ethyl acetate were added. The aqueous layer was extracted a second time with ethyl acetate and then acidified with, hydrochloric acid and extracted again. The combined ethyl acetate extract was washed with saturated sodium chloride solution, dried with MgSO4, and evaporated to a gum. Column chromatography of the latter (Merck silica gel eluted with 1:1:2 ethyl acetate/methylene chloride/hexane) gave 200 mg of product (80%).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([O:42][CH3:43])[CH:35]=3)=O)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1>C1COCC1>[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([O:42][CH3:43])[CH:35]=3)=[CH:9][C:10]#[N:11])=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: COc1cc(OC)cc(C(=O)c2ccc3c(c2)OCCO3)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Temperature: 0 °C
Yield: 88.4 %

Procedure:
To a stirred solution of cyanomethylphosphonic acid diethyl ester (1.08 ml, 6.86 mmol) in anhydrous THF (10 ml) in an ice bath was added lithium bis-(trimethylsilyl)amide (1.0 M solution in THF, 6.86 ml, 6.86 mmol) slowly. The mixture was stirred at rt for 40 min, before a solution of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanone (1.03 g, 3.43 mmol) in anhydrous THF (20 ml) was added. The mixture was refluxed overnight. The solution was poured into ice water (20 ml) and the two phases were separated. The THF phase was evaporated and combined with the aqueous phase, which were then extracted with CH2Cl2 (2×40 ml), washed with water (50 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography 5% EtOAc in hexane gradient to 25% EtOAc in hexane) to give 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile as an oil (0.98 g, 88%): 1H NMR (DMSO-d6) δ 6.99-6.79 (m, 3H, Ar), 6.65-6.62 (2ts, 1H, Ar), 6.46-6.44 (2ds, 2H, Ar), 6.25 (s, 0.47H, double bond proton of one isomer), 6.20 (s, 0.54H, double bond proton of the other isomer), 4.33-4.24 (m, 4H, 2CH2), 3.76 (s, 3H, OCH3), 3.74 (s, 3H, OCH3); 13C NMR (DMSO-d6) δ 179.5, 160.8, 160.7, 145.7, 144.8, 143.3, 143.0, 140.3, 139.1, 130.4, 129.7, 122.5, 121.7, 118.2, 118.1, 117.9, 117.2, 117.1, 116.6, 107.1, 106.7, 101.8, 100.9, 95.4, 94.3, 64.4, 64.2, 64.0, 64.0, 55.4, 54.9; Anal. Calcd. For C19H17NO4 (+0.05 H2O): C, 69.40; H, 5.26; N, 4.24. Found: C, 69.19; H, 5.11; N, 4.25.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[N+:8]([C:11]1[C:12]([N:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]2)=[C:13]2[CH2:20]CC[C:14]2=[N+:15]([O-])[CH:16]=1)([O-:10])=[O:9]>>[C:5]([O:4][CH:1]1[C:14]2=[N:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]([N:21]3[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:34])[CH2:22]3)=[C:13]2[CH2:20][CH2:2]1)(=[O:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 90 °C
Yield: 21.7 %

Procedure:
A mixture of acetic anhydride (0.90 g, 8.8 mmol) and tert-butyl [(3S)-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (270.0 mg, 0.7135 mmol) was sealed and heated at 90° C. for 1 h, then allowed to cool. After cooling, the excess acetic anhydride was removed under reduced pressure, the residue was dissolved in DCM, then poured into ice cold Na2CO3. The mixture was extracted twice with DCM, the combined extracts were dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to provide the sub-title compound as yellow powder (65 mg, 22%). LCMS calc. for C20H29N4O6 (M+H)+: m/z=421.4. Found: 421.3.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:14])([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]([O:13][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:14])[CH2:11][O:12][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CC(O)(CO)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(COCc1ccccc1)(COCc1ccccc1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
1 Benzyloxymethyl-1-methylethane-1,2-diol (2g) in dimethyl formamide (25 ml) was treated with a slight excess of sodium hydride (0.6g) at ambient temperature for 1h, then 90° for 15 mins. The product was then treated with benzyl chloride (4g) and 1,2,3-tribenzyloxy-2-methylpropane was isolated by evaporation of the solvent followed by chromatography on silica gel eluted with 9/1 methylene chloride/ether. The desired product was a colourless oil whose structure was confirmed by n.m.r.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[C:27]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:27]([C:31]1[CH:36]=[CH:35][C:34]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1nc(C)n(-c2ccc(C(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (4-tert-butylphenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylene chloride (10 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.12 g, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:21]1[N:22]([CH3:33])[C:23](=[O:32])[C:24]([CH3:31])=[CH:25][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:21]2[N:22]([CH3:33])[C:23](=[O:32])[C:24]([CH3:31])=[CH:25][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: COC(=O)c1cc(C)c(=O)n(C)c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of 4-bromo-2-fluorobenzenamine (0.058 g, 0.31 mmol) in THF (2 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (0.56 mL, 0.56 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for one hour at −78° C. Methyl 2-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.060 g, 0.28 mmol) was then added dropwise as a solution in THF (1 mL) and the reaction mixture was stirred for 25 minutes at −78° C. The reaction mixture was quenched by the addition of H2O and the pH was adjusted with 0.1M HCl and then diluted with EtOAc and saturated NaCl and the layers separated. The aqueous layer was back extracted with EtOAc (1×). The combined EtOAc layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 20:1) gave 0.086 g (84%) pure desired product as a white crystalline solid. MS ESI (+) m/z 371, 373 (M+, Br pattern) detected; 1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 7.79 (s, 1H), 7.32 (d, 1H), 7.18 (d, 1H), 6.58 (t, 1H), 3.85 (s, 3H), 3.29 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: COC1C=CC(C[S:8][CH2:9][CH:10]2[CH2:15][CH:14]([CH2:16][S:17]CC3C=CC(OC)=CC=3)[O:13][C:11]2=[O:12])=CC=1.N>CO.C1COCC1>[SH:8][CH2:9][CH:10]1[CH2:15][CH:14]([CH2:16][SH:17])[O:13][C:11]1=[O:12]
Reactant: COc1ccc(CSCC2CC(CSCc3ccc(OC)cc3)C(=O)O2)cc1
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: O=C1OC(CS)CC1CS
Temperature: 25 °C
Reaction time: 8 h
Yield: 230.9 %

Procedure:
Into a solution of 2,4-bis(4-methoxybenzylthiomethyl)-4-butanolide (mixture of cis and trans forms, 2.40 g) in a mixture of methanol (30 ml) and THF (10 ml), ammonia gas was bubbled for 30 minutes under ice-cooling. The mixture was stirred overnight at room temperature and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 2.36 g (94%) of the following compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:29](OC)(OC)(OC)[CH2:30][CH2:31][CH3:32]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:30]([C:29]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:31][CH3:32]
Reactant: CCOC(=O)CCCCCCCCCCCNc1c(N)cnc2ccccc12
Reactant: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)OCC
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Ethyl 12-(3-aminoquinolin-4-ylamino)dodecanoate (20.0 g, 51.8 mmol) was treated according to a modification of the method described in Part B of Example 8. Prior to the addition of trimethyl orthobutyrate (9.53 mL, 59.6 mmol) and pyridinium p-toluenesulfonate (0.500 g, 1.99 mmol), the reaction was heated at reflux for ten minutes. After the reaction was heated at reflux, it was allowed to cool to ambient temperature, washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure to provide 22.3 g of ethyl 12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanoate, which was used without purification.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH2:4][O:5][C:6]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]=2[C:8]=1[C:9]([O:11]CC)=[O:10].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH2:4][O:5][C:6]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]=2[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C1=C(C(F)(F)F)COc2ccc3ccccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=C(C(F)(F)F)COc2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
A solution of the ester from Step 1 (0.8 g, 2.5 mmol) was dissolved in 40 mL of ethanol and 10 mL of tetrahydrofuran, treated with sodium hydroxide (2.5 N, 10 mL, 25 mmol) and stirred at room temperature for 16 hours. The reaction mixture was acidified with 1.0 N HCl, whereupon a solid formed that was isolated by filtration. The solid was washed with 20 mL of water to afford 0.7 g (95%) of the title compound as a yellow solid: mp 245.9–248.6° C. 1H NMR (acetone-d6/300 MHz) 8.57 (s, 1H), 8.28 (d, 1H, J=8.7 Hz), 8.03 (d, 1H, J=9.0 Hz), 7.93 (d, 1H, J=8.7), 7.67 (m, 1H), 7.50 (m, 1H), 7.28 (d, 1H, J=9.0), 5.96 (qH-F, 1H, J=7.2 Hz). FABHRMS m/z 295.0561 (M+H, Calc'd 295.0582). Anal. Calc'd for C15H9O3F3+3.31% H2O: C, 59.21; H, 3.35. Found: C, 59.17; H, 3.07.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:11]([N:14]=[C:15]([NH2:29])[NH:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[N:18]=1)[CH2:12][CH3:13]>CCO.C(N(CC)CC)C>[CH2:11]([N:14]=[C:15]([NH2:29])[NH:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[N:18]=1)[CH2:12][CH3:13]
Reactant: CCCN=C(N)Nc1ccnc(CCCCCN)n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCN=C(N)Nc1ccnc(CCCCCNC(=O)c2cccnc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.4 %

Procedure:
Nicotinoyl chloride hydrochloride (0.2 g.) was added at 0° to a stirred solution of 4-(2-propylguanidino)-2-(5-aminopentyl)pyrimidine (0.2 g.) in EtOH (5 ml.) and triethylamine (2 ml.). The mixture was stirred at room temperature for 16 hours and evaporated to dryness. The residue was partitioned between 2N aqueous HCl and EtOAc and the aqueous phase was then basified with 10N aqueous NaOH and extracted with EtOAc. The extract was dried (MgSO4) and evaporated to dryness. The residual gum was purified twice by preparative thin layer chromatography on Merck 60 F-254 plates using EtOAc/MeOH/aqueous ammonia (s.g. 0.88) 6:1:1 v/v/v as developing solvent. The appropriate zone of the chromatogram was extracted with MeOH/aqueous ammonia (s.g. 0.88) 10:1 v/v and the solvent was evaporated. The residual gum was dissolved in EtOAc, filtered and treated with an excess of a saturated solution of maleic acid in EtOAc. The precipitated gum was washed with EtOAc to give N-[5-(4-[2-propylguanidino]-pyrimid-2-yl)pentyl]nicotinamide (0.015 g.) as a straw coloured gum. The n.m.r. spectrum in d4MeOH using tetramethylsilane as standard included the following resonances (δ): 1.0 (3H, triplet), 1.7 (8H, multiplet), 2.9 (2H, triplet), 3.6 (2H, triplet), 6.8 (1H, doublet), 7.6 (1H, multiplet), 8.3 (2H, multiplet) and 8.8 (2H, complex).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[OH:9][CH:8]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCCc1ccc(C(=O)Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCc1ccc(C(O)Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a suspension of 20.0 g of methyl 4-[4-(phenylacetyl)phenyl]butyrate in 200 ml of methanol, 2.52 g of sodium borohydride was added portionwise under ice-cooling, and stirring was continued for 1 hour. After the reaction solvent was removed under reduced pressure, the residue was added with water and then extracted with ether. After the ether layer was washed with water and dried, the solvent was removed to yield 20.3 g of pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=O.[CH3:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=1)=[O:17].[OH-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:15]/[C:16]([C:18]2[CH:19]=[C:20]([O:26][CH3:27])[CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCOc1ccc(C=O)cc1O
Reactant: COc1cc(OC)cc(C(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(/C=C/C(=O)c2cc(OC)cc(OC)c2)cc1O
Yield: 48.1 %

Procedure:
A mixture of 3-hydroxy-4-butoxybenzaldehyde (0.4 g, 2.1 mmol), 3,5-dimethoxyacetophenone (0.371.9, 2.1 mmol) and 50% w/v of aqueous sodium hydroxide (3.3 ml, 0.206 mol) in methanol (10 ml) at room temperature for 18 h. The yellow solid that precipitated was filtered and sequentially washed with cold methanol and ether and finally dried in a vacuum dessicator. Purification was achieved using column chromatography (SiO2, petroleum:ether (40:60 v/v) with an increasing gradient of ethyl acetate) which gave 0.36 g (50%) of a yellow solid: 1H-NMR (CDCl3) δ 7.7 (d, 1H), 7.3 (m, 2H), 7.1 (d, 3H), 6.8 (d, 1H), 6.7 (t, 1H), 5.7 (s, 1H), 4.1 (t, 2H), 3.9 (s, 6H), 1.8 (m, 2H), 1.5 (m, 2H), 1.0 (t, 3H). 13C-NMR (CDCl3) δ 190.0, 160.9, 148.3, 146.0, 144.9, 140.5, 128.4, 122.6, 120.2, 112.9, 111.4, 106.2, 104.9, 68.8, 55.6, 31.1, 19.1. 13.7. Mass Spectrum m/e (M+1) 357. Anal. Calcd. for C21H24O5: C, 70.77, H, 6.79. Found C, 70.84; H, 6.81.