Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: OB(O)c1ccco1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccco2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E106) (100 mg, 0.22 mmol) and 2-furanylboronic acid (50 mg, 0.45 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated in vacuo and purified using an SCX cartridge eluting with methanol followed by ammonia (2M in methanol). The appropriate fractions were combined and evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E109). MS (ES+) m/e 442 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[C:17]([N:19]([CH3:25])[C:20](=[O:24])[CH:21](Br)[CH3:22])#[N:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[I-].[K+]>[C:17]([N:19]([CH3:25])[C:20](=[O:24])[CH:21]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[C:4]([F:16])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:14][CH:13]=1)[CH3:22])#[N:18]
Reactant: CC(Br)C(=O)N(C)C#N
Reactant: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)N(C)C#N
Temperature: 80 °C
Yield: 87.2 %

Procedure:
48.0 g (0.20 mole) of 4-(5-chloro-3-fluoropyridin-2-yloxy)phenol and 38.2 g (0.20 mole) of 2-bromopropionic acid N-cyano-N-methylamide are dissolved in 400 ml of acetonitrile. 35.9 g (0.26 mole) of potassium carbonate and 0.33 g (0.002 mole) of potassium iodide are added to the solution and the reaction mixture is heated for 13 hours at 80° C. The precipitate is removed by filtration, the filtrate is concentrated by evaporation and the residue is taken up in 500 ml of methlyene chloride. The solution is purified by treatment with activated carbon and filtration through silica gel. The filtrate is concentrated by evaporation and the residue is crystallised from a mixture of hexane and ethyl acetate, affording 61 g of 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionic acid N-cyano-N-methylamide.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[Cl:4].[Cl:7][SiH:8]([Cl:10])[Cl:9]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:7][Si:8]([Cl:10])([Cl:9])[CH2:2][Si:3]([Cl:4])([CH3:6])[CH3:5]
Reactant: C[Si](C)(Cl)CCl
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: C[Si](C)(Cl)C[Si](Cl)(Cl)Cl
Yield: 60 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.27 g (1.5 mmol) of tetrabutylphosphonium chloride, 2.15 g (15.0 mmol) of (chloromethyl)dimethylchlorosilane, and 6.10 g (45.0 mmol) of trichlorosilane were reacted at 150° C. for 10 hrs. The resulting mixture was distilled to give 2.18 g of 1,1,1,3-tetrachloro-3-methyl-1,3-disilabutane (yield; 60%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[CH:20]=[CH:21][C:22](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][CH:27]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(C(F)(F)F)c3)nc2n(CC)c1=O

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.0 g (13.9 mmol) of 3-trifluoromethylcinnamic acid. Then, the resultant crude crystals were recrystallized from acetonitrile/water to give 2.07 g (yield of Compound 156 as white needles.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]([O:20][CH3:21])[C:11]=1[CH2:22][CH:23]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:26]([NH:25][CH2:23][CH2:22][C:11]1[C:12]([O:20][CH3:21])=[N:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]=1[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1CC=O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1CCNC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of the compound from Step H above (1.55 g, 4.26 mmol), aminodiphenylmethane (1.11 mL, 6.40 mmol), and powdered 4 Å molecular sieves (2.80 g) in dichloromethane (20 mL) was stirred for 30 min. Then sodium triacetoxyborohydride (132 mg, 0.625 mmol) was added. The resultant mixture was stirred overnight, diluted with dichloromethane, filtered, and the filtrate was washed with saturated aqueous sodium carbonate solution. The layers were separated, and the aqueous solution was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by flash chromatography (silica gel; dichloromethane as eluant) to yield the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.48 (s, 1H), 7.18-7.38 (m, 10H), 4.84 (s, 1H), 4.78 (s, 2H), 3.81 (s, 3H), 2.77 (m, 4H), 1.62 (br s, 1H), 0.97 (s, 9H), 0.12 (s, 6H). LC/MS: 531 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:19]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29]([OH:31])=O)=[N:18][CH:17]=[N:16][C:15]=3[S:14][CH:13]=2)=[CH:8][CH:7]=1.[NH2:35][NH2:36]>O1CCCC1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:20]3[C:19]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29]([NH:35][NH2:36])=[O:31])=[N:18][CH:17]=[N:16][C:15]=3[S:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)c1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Reactant: NN
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NNC(=O)c1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Thionyl chloride (13 mg, 0.11 mmol) was added to a solution of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzoic acid (43 mg, 0.10 mmol) in tetrahydrofuran (2.0 mL) with stirring at 70° C. Stirring continued for one hour at 70° C. and then the mixture was cooled to 25° C. and added to a solution of hydrazine (32 mg, 1.0 mmol) in tetrahydrofuran (2.0 mL). The reaction was stirred at room temperature for one hour and the solvent was then removed in vacuo. The residue was dissolved in ethyl acetate (30 mL), washed with of aqueous sodium bicarbonate solution (20 mL), concentrated, and purified by column chromatography over silica gel using 2% methanol in ethyl acetate as eluant to give 22 mg (50%) of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzohydrazide as a white solid. MS [M+H] 439.2, 1H NMR (CDCl3) δ (ppm) 8.65 (s, 1H), 7.50-7.35 (m, 2H), 7.32-7.21 (m, 3H), 7.18 (s, 1H), 7.10-6.97 (m, 2H), 6.94 (d, J=2.7 Hz, 1H), 4.59 (t, J=6.9 Hz, 2H), 4.11 (s, 2H), 3.74 (t, J=6.0 Hz, 2H), 2.09 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[CH2:22][CH2:21][N:20]([CH3:23])[C:19](=[O:24])[C:9]3=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[C:5](=[O:25])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)(Cl)Cl>[CH2:12]([O:11][C:10]1[C:6]2[C:5](=[O:25])[N:4]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:3]=[C:2]([NH:1][C:43](=[O:45])[CH3:44])[C:7]=2[N:8]2[CH2:22][CH2:21][N:20]([CH3:23])[C:19](=[O:24])[C:9]=12)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(N)c32)C1=O
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-amino-2-(4-fluorobenzyl)-10-benzyloxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (21 mg, 47 μmol) and diisopropylethylamine (10 μL, 56 μmol) in anhydrous chloroform (2 mL), acetyl chloride (8 μL, 104 μmol) was added. The mixture was stirred at room temperature for 30 minutes and concentrated under vacuum. The intermediate bisacetylated product was dissolved in methanol, stirred at room temperature overnight, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel. Collection and concentration of appropriate fractions provided the title monoacetylated product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][CH2:11][CH2:10][C:8]3=2)[CH:3]=[C:2]1C(O)=O.O1C2C=C3C(CCN3)=CC=2C=C1C(O)=O.CCCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][CH2:11][CH2:10][C:8]3=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1cc2ccc3c(c2[nH]1)CCO3
Agent: O=C(O)c1cc2cc3c(cc2o1)NCC3
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCCC
Product: c1cc2ccc3c(c2[nH]1)CCO3
Temperature: 25 °C
Yield: 5.4 %

Procedure:
A stirred solution of 7,8-dihydrofuro[2,3-g]indole-2-carboxylic acid and 5,6-dihydrofuro[3,2-f]indole-2-carboxylic acid (1:1) (5.46 g, 26.9 mmol) in phenyl ether (250 mL) was heated at reflux for 45 min, then allowed to cool to ambient temperature. Heptane (500 mL) was added and the mixture was passed through a heptane-packed SiO2 column under pressure. The column was eluted with heptane (1.5 L), then heptane-dichloromethane (1:1, 1L) and finally dichloromethane to afford 7,8-dihydrofuro[2,3-g]indole (230 mg, 5.4%) as a white solid. IR νmax (Nujol)/cm−1 3382, 2925, 2854, 1644, 1618, 1497, 1463, 1441, 1435, 1368, 1326, 1234, 1140, 1021, 970, 793, 719, 622, 533 and 475; NMR (400 MHz, CDCl3) δH 3.31 (2H, t, J 8.5 Hz), 4.66 (2H, t, J 8.5 Hz), 6.51 (1H, dd, J 2, 3.5 Hz), 6.73 (1H, d, J 8 Hz), 7.06 (1H, dd, J 2, 3.5 Hz), 7.39 (1H, d, J 8.5 Hz) and 7.83 (1H, brs). Also collected were 5,6-dihydrofuro[3,2-f]indole (667 mg, 15.6%) and mixed fractions (2.94 g, 68.7%). The mixed isomers were further separated by flash column chromatography [SiO2; ethyl acetate-heptane (1:3)] to afford afford 7,8-dihydrofuro[2,3-g]indole (408 mg, 9.5%) as a white solid and 5,6-dihydrofuro[3,2-f]indole (690 mg, 16%).
Reaction SMILES: CC([O-])(C)C.[Na+].[NH2:7][C:8]1[CH2:9][N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH2:12][C:13]=1[C:14]([O:16]CC)=O.[CH3:26][O:27][CH:28]([O:34]C)[CH2:29][C:30](OC)=O>C1COCC1>[CH3:26][O:27][C:28]([C:29]1[CH:30]=[N:7][C:8]2[CH2:9][N:10]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:11][CH2:12][C:13]=2[C:14]=1[OH:16])=[O:34]
Reactant: COC(=O)CC(OC)OC
Reactant: CCOC(=O)C1=C(N)CN(Cc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc2c(c1O)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a suspension of NaOtBu (4.23 g, 34.57 mM) in THF (50 mL) was added a mixture of ethyl 3-amino-1-benzyl-1,2,5,6-tetrahydropyridine-4-carboxylate (3.0 g, 11.52 mM) and methyl 3,3-dimethoxypropanoate (5.12 g, 34.57 mM) in THF (20 mL) in one portion and the mixture was agitated at ambient temperature overnight. The mixture was concentrated to half the volume before being quenched with ice-cold water. The homogeneous solution was extracted ethyl ether and the aqueous layer was carefully acidified with HCl until acidic. The precipitate was filtered, washed with water, and dried under vacuum to obtain the title compound as an off-white solid (1.6 g, 47%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[O:16]1[CH:18]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:17]1>CN(C)C=O>[F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[N:6]([CH2:17][CH:18]([OH:16])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:7]=1
Reactant: Nc1nc(=O)[nH]cc1F
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(O)Cn1cc(F)c(N)nc1=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
A mixture of 5-fluorocytosine (0.80 g, 6.20 mmol), anhydrous potassium carbonate (40 mg) and anhydrous dimethyl formamide (15 mL) is heated to 70° C. under a nitrogen atmosphere. Then rac-1,2-epoxy-3-octadecyloxypropane (2.0 g, 6.13 mmol) is added to this mixture with stirring over a period of 1 hour. The resultant reaction mixture is stirred at 80°-90° C. (oil bath temperature) for 48 hours. The reaction mixture is cooled to room temperature and concentrated under reduced pressure (0.5 mm Hg) to afford the crude product as a cream solid. This crude material is purified by chromatography and dried in vacuo to give 0.6 g (22%) 5-fluoro-1-[2'-hydroxy-3'-octadecyloxypropyl]-cytosine (CPR 1152): Thin-layer Chromatography (TLC; 4×8 cm silica gel 60, 0.25 mm thickness): 8:2 (v/v) CHCl3 -CH3OH (Rf value=0.75); mp 118°-119° C.
Reaction SMILES: [O:1]=[C:2]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25][CH2:24]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[H][H]>C(O)C.[C].[Pd]>[OH:1][CH:2]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25][CH2:24]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1
Reactant: [H][H]
Reactant: O=C1CCc2cc(C(=O)CCCN3CCN(c4ccc([N+](=O)[O-])cc4)CC3)ccc2N1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCN(CCCC(O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1

Procedure:
1.5 Gram of 6-{1-oxo-4-[4-(4-nitrophenyl)-piperazinyl]-butyl}-3,4-dihydrocarbostyril and 0.3 g of 5%-palladium-carbon were dispersed in 150 ml of ethanol and catalytically reduced under 2 kg/cm2 of hydrogen gas for 5 hours. The reaction mixture was filtered and the mother liquor was concentrated under a reduced pressure. The residue thus obtained was recrystallized from methanol to obtain 0.7 g of 6-{1-hydroxy-4-[4-(4-aminophenyl)-1-piperazinyl]butyl}- 3,4-dihydrocarbostyril in brown powdery crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([O:25][CH:26]([CH3:28])[CH3:27])[CH2:6][C:7]1[CH:15]=[C:14]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]2[O:11][CH:12]=[CH:13][C:9]=2[CH:8]=1)[CH3:2]>C(O)C.[H][H].[C].[Pd]>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([O:25][CH:26]([CH3:28])[CH3:27])[CH2:6][C:7]1[CH:15]=[C:14]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:10]2[O:11][CH2:12][CH2:13][C:9]=2[CH:8]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(Cc1cc(CNC(=O)OC(C)(C)C)c2occc2c1)OC(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1cc2c(c(CNC(=O)OC(C)(C)C)c1)OCC2)OC(C)C
Yield: 92.6 %

Procedure:
29 mg of 3-(7-[(t-butoxycarbonyl)amino]methylbenzo[b]furan-5-yl)-2-isopropoxypropionic acid ethyl ester was dissolved in ethanol, and 30 mg of 10% palladium carbon was added, followed by stirring for 3 days at room temperature in hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated, to give 27 mg of 3-(7-[(t-butoxycarbonyl)amino]methyl-2,3-dihydrobenzo[b]furan-5-yl)-2-isopropoxypropionic acid ethyl ester was obtained.
Reaction SMILES: [NH:1]([C:5]1[CH:36]=[CH:35][CH:34]=[CH:33][C:6]=1[CH2:7][C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)[C:10]=2[N:9]=1)[C:2]([CH3:4])=[O:3].O.NN.[H][H]>[Pd]>[NH:1]([C:5]1[CH:36]=[CH:35][CH:34]=[CH:33][C:6]=1[CH2:7][C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=3)[C:10]=2[N:9]=1)[C:2]([CH3:4])=[O:3]
Reactant: CCCn1c(=O)c2[nH]c(Cc3ccccc3NC(C)=O)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2[nH]c(Cc3ccccc3NC(C)=O)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 2, 2-(acetamino)phenylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 8-(2-acetaminobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine. By methods well known in the art, 8-(2-acetaminobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 8-(2-acetaminobenzyl)-3-[2-(4-aminophenyl)ethyl]-1-propylxanthine.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C:21]1([C:29]([OH:31])=[O:30])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][N:19]([CH2:20][C:21]1([C:29]([OH:31])=[O:30])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[CH:1]=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)CCC(CNOCc2ccccc2)(C(=O)O)CC1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC1(C)CCC(CN(C=O)OCc2ccccc2)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a cold solution of formic acid (12.8 mL, 0.33 mol) in dichloromethane (50 mL) at 0° C. under a nitrogen atmosphere was added acetic anhydride (4.8 mL, 51 mmol). After 1 h, a solution of 1-(benzyloxyamino-methyl)-4,4-dimethyl-cyclohexanecarboxylic acid from Preparation 30 (5.11 mmol theoretical) in dichloromethane (50 mL) was added. The reaction was stirred at room temperature for 18 h and was concentrated in vacuo. Water (100 mL) was added and the mixture was extracted with dichloromethane (50 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo to yield the title compound (1.55 g, 95%). MH+320.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Fc1cc(F)cc(Sc2ccc(Br)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3cc(F)cc(F)c3)cc2)c1C
Yield: 36.2 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-3,5-difluorobenzene (0.184 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(3,5-difluoro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.09 g, 36%) as a solid. MS calcd. for C26H18F3O2S [(M−H)−] 451, obsd. 451.2.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:10]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].N([O-])=O.[Na+].C(#N)C.O.[ClH:28]>O.Cl[Cu]>[Br:9][C:6]1[CH:5]=[C:4]([CH:10]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=[C:2]([Cl:28])[C:7]=1[OH:8]
Reactant: Cl
Reactant: CCOC(=O)C(CC(C)C)c1cc(N)c(O)c(Br)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(O)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate 1 (4 g, 0.012 mol) was dissolved in a mixture of ACN/H2O/HCl 60 mL/30 mL/8 mL at 0° C. A solution of NaNO2 (0.919 g, 1.1 eq) in water (10 mL) was added dropwise at 0° C. and the reaction mixture was stirred for 1 h at 0° C. A solution of CuCl (5.99 g, 0.060 mol) in water (10 mL) was added dropwise to the reaction mixture at 0° C. The reaction mixture was then heated to 50° C. for 2.5 h. upon which the mixture was poured into ice water, extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with water (200 mL) and brine (100 mL), dried over NaSO4 and concentrated in vacuo to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate as yellow oil 2.2 g, (47.3%). 1H NMR (CDCl3, 200 MHz): 7.38 (s, 1H); 7.4 (s, 1H); 5.80 (bs, 1H); 4.13 (q, 2H); 3.51 (t, 1H); 1.93-1.56 (m, 2H); 1.51 (m, 1H); 1.21 (t, 3H), 0.97 (d, 6H);