Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:13]=[C:12]([OH:14])[C:11]3[CH2:15][CH2:16][CH2:17][C:10]=3[N:9]=2)[CH:7]=1.C(C1C=CN(C2C=C(O[CH:38]3[CH2:55][CH:54]4[CH:40]([C:41](=[O:67])[N:42]([CH3:66])[CH2:43][CH2:44][CH2:45][CH2:46][CH:47]=[CH:48][CH:49]5[C:51]([C:57]([NH:59][S:60]([N:63]([CH3:65])[CH3:64])(=[O:62])=[O:61])=[O:58])([NH:52][C:53]4=[O:56])[CH2:50]5)[CH2:39]3)C3C(=C(C)C(OC)=CC=3)N=2)N=1)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:13]=[C:12]([O:14][CH:38]3[CH2:55][CH:54]4[CH:40]([C:41](=[O:67])[N:42]([CH3:66])[CH2:43][CH2:44][CH2:45][CH2:46][CH:47]=[CH:48][CH:49]5[C:51]([C:57]([NH:59][S:60]([N:63]([CH3:64])[CH3:65])(=[O:61])=[O:62])=[O:58])([NH:52][C:53]4=[O:56])[CH2:50]5)[CH2:39]3)[C:11]3[CH2:15][CH2:16][CH2:17][C:10]=3[N:9]=2)[CH:7]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)N(C)C)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)C)n3)nc2c1C
Reactant: Oc1nc(-c2cc(Br)ccc2F)nc2c1CCC2
Product: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)N(C)C)NC(=O)C2CC(Oc3nc(-c4cc(Br)ccc4F)nc4c3CCC4)CC2C1=O

Procedure:
The title compound was prepared from 2-(5-bromo-2-fluorophenyl)-4-hydroxy-6,7-dihydro-5H-cyclopentapyrimidine and intermediate 24 following the procedure (Steps 13-16) reported for the preparation of N-[17-[2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo-[13.3.0.04,6]octadec-7-ene-4-carbonyl](dimethylamino)sulfonamide (29): m/z=748 (M+H)+. 1H NMR (CDCl3): 1.13-1.51 (m, 4H), 1.54-1.95 (m, 4H), 2.08-2.45 (m, 5H), 2.50-2.65 (m, 2H), 2.80-3.15 (m, 14H), 3.22-3.40 (m, 2H), 4.60 (t, J=12.4 Hz, 1H), 5.05 (t, J=9.9 Hz, 1H), 5.60-5.75 (m, 2H), 6.24 (s, 1H), 7.05 (t, J=9.5 Hz, 1H), 7.48-7.55 (m, 1H), 8.10-8.18 (m, 1H), 10.6 (br s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].OC1C2C(=C(O)C=CC=2)C=CC=1.[C:19]([O:22][CH:23]=[CH2:24])(=O)[CH3:20].OC1C2[C:30](=[C:31]([O:36][CH:37]=[CH2:38])[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH:23]([O:22][C:19]1[C:20]2[C:30](=[C:31]([O:36][CH:37]=[CH2:38])[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)=[CH2:24]
Reactant: C=COc1cccc2c(O)cccc12
Reactant: C=COC(C)=O
Agent: O=C([O-])[O-]
Agent: Oc1cccc2c(O)cccc12
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COc1cccc2c(OC=C)cccc12
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (67 mg, 0.1 mmol) and sodium carbonate (640 mg, 6 mmol) in toluene (5 ml) were added 1,5-dihydroxynaphthalene (5 mmol) and vinyl acetate (2.15 g, 25 mmol), followed by stirring at 100° C. in an atmosphere of argon gas for 6 hours. The reaction mixture was analyzed by gas chromatography to find that 1-hydroxy-5-vinyloxynaphthalene and 1,5-bis(vinyloxy)naphthalene were formed in yields of 15% and 13%, respectively, with a conversion from 1,5-dihydroxynaphthalene of 30%.
Reaction SMILES: [C:1]1([C:7]2[C:8](C(O)=O)=[C:9](C(O)=O)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>N1C2C(=CC=CC=2)C=CC=1>[C:12]1([C:11]2[NH:10][CH:9]=[CH:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1[nH]c(-c2ccccc2)c(-c2ccccc2)c1C(=O)O
Solvent: c1ccc2ncccc2c1
Product: c1ccc(-c2cc[nH]c2-c2ccccc2)cc1

Procedure:
A mixture of 20 g (0.065 mole) of 4,5-diphenylpyrrole-2,3-dicarboxylic acid in 80 ml quinoline was heated at reflux in an oil bath (bath ~230°) until gas evolution stopped (approx. one-half hour). The reaction mixture was cooled and most of the quinoline was removed by distillation (bp 58° @ 0.2 mm). The partially crystalline residue was chromatographed on 300 g Silic AR CC-7, eluting with toluene to give 12 g (85%) of faintly pink 2,3-diphenylpyrrole which could be further purified by recrystallization from ethanol/water or by sublimation (~125° @ 0.2 mm) to give white solid, m.p. 132°-3°.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:29]=[CH:28][C:9]2[C:10]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)=[N:11][O:12][C:8]=2[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[C:36]([Cu])#[N:37]>O.Cl.C1(C)C=CC=CC=1>[C:36]([C:6]1[CH:29]=[CH:28][C:9]2[C:10]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)=[N:11][O:12][C:8]=2[CH:7]=1)#[N:37]
Reactant: N#C[Cu]
Reactant: Nc1ccc2c(CCC3CCN(Cc4ccccc4)CC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(CCC3CCN(Cc4ccccc4)CC3)noc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A solution of NaNO2 (0.112 g, 1.62 mmol) in H2O (4 mL) was added to a solution of 6-amino-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole (0.534 g, 1.59 mmol) in 28% HCl (20 mL) kept at 0° C. The resulting mixture was neutralized to pH 7 by cautious addition of solid Na2CO3. The neutral mixture was added in portions to a well-stirred mixture of toluene (75 mL), ice, and a freshly prepared solution of CuCN (Organic Synthesis, Coll. Vol. I, p. 514; CuSO4 :0.318 g, 1.99 mmol). The mixture obtained was kept at 0° C. for 30 minutes, then at room temperature for 2 hours, and finally, heated at 50° C. for 5 minutes. The mixture was extracted with ethyl acetate and the organic phase was washed with H2O, brine, dried (MgSO4), filtered, and concentrated. Purification by silica gel flash chromatography (3% MeOH-CH2Cl2) gave the title compound (0.236 g, 43%) as a pale orange solid. Recrystallization (EtOH-hexanes) of a small sample gave the title compound as an off-white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH2:19][OH:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH:19]=[O:20])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3(CO)CCOCC3)cc2C2=CCCCC2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3(C=O)CCOCC3)cc2C2=CCCCC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
A mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(4-hydroxymethyl-tetrahydro-pyran-4-yl)-phenyl]-amide (as prepared in Example 20, 75.4 mg, 0.185 mmol), Dess-Martin periodinane (157 mg, 0.369 mmol) and NaHCO3 (155 mg, 1.85 mmol) in 3 mL of DCM was stirred at 0° C. for 0.5 h, at RT for 1 h. To the reaction was added 2 mL of 10% Na2S2O3 and the resulting mixture was stirred vigorously for 5 min. The mixture was treated with 20 mL of H2O and extracted with EtOAc (2×40 mL). The combined organic layers were washed with saturated NaHCO3 aqueous solution (10 mL), H2O (10 mL) and brine (10 mL). After drying over Na2SO4 and concentrating in vacuo, the residue was purified by silica gel chromatography (10-20% EtOAc/DCM) to afford the title compound (45 mg, 60%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C23H24N4O3, 405.2 (M+H). found 405.1.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:12]1([C:18]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[S:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:1]1([CH2:7][C:8]([N:24]2[CH2:25][CH:26]3[C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:19][CH2:20][S:21][CH:22]3[CH2:23]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2(c3ccccc3)CCSC3CNCC32)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N1CC2SCCC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 1.15 cm3 of phenylacetyl chloride in 25 cm3 of dichloromethane is added over 5 minutes to a solution, cooled to 0° C., of 2.63 g of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride and 2.42 cm3 of triethylamine in 25 cm3 of dichloromethane. After stirring for one hour at 0° C. and one hour at 20° C. 20 cm3 of dichloromethane are added. The reaction mixture is washed twice with 100 cm3 of distilled water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (0.04-0.06 mm, diameter 3.5 cm, height 26 cm), eluting under a nitrogen pressure of 0.4 bar with a cyclohexane and ethyl acetate mixture (80/20 by volume) and collecting fractions of 125 cm3. Fractions 19 to 26 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 0.87 g of (4aRS,7aRS)-6-phenylacetyl-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole is obtained in the form of a white solid; melting point 210° C.
Reaction SMILES: [C:1]1([Si:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:21]=[N+:22]=[N-:23].[Li+]>O1CCCC1>[C:1]1([Si:7]([N:21]=[N+:22]=[N-:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: C1CCOC1
Product: [N-]=[N+]=N[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 86.3 %

Procedure:
Following the method of Wiberg et al [Wiberg et al, Angew. Chem. Internat'l Ed.Engl., 1, 335 (1962)] in an inert atmosphere enclosure a solution of triphenylsilylchloride (73.9 g, 0.251 mol) in tetrahydrofuran (400 ml) was stirred with lithium azide (15.3 g, 0.312 mol) at room temperature over a period of 115 hr. After filtration, the solvent was removed in vacuo. The resulting white solid was boiled with heptane (350 ml), filtered hot and allowed to crystallize. Triphenylsilyl azide, 65.5 g (86.3% yield), mp 82°-84° C. was obtained. The melting point and infrared spectrum were identical with that of an authentic sample.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][C:13]=1[OH:24].[C:25]([O-])([O-])=O.[K+].[K+].IC>CCO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:22])[CH3:23])(=[O:19])=[O:20])=[CH:14][C:13]=1[O:24][CH3:25]
Reactant: CN(C)S(=O)(=O)c1ccc(N2C(=O)c3ccccc3C2=O)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: COc1cc(S(=O)(=O)N(C)C)ccc1N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
A suspension of 4-(1,3-dioxoisoindolin-2-yl)-3-hydroxy-N,N-dimethylbenzenesulfonamide (Preparation 106, 83 mg, 0.240 mmol), K2CO3 (50 mg, 0.359 mmol) and iodomethane (0.1 mL, 1.60 mmol) in EtOH (4 mL) was stirred at 100° C. under microwave irradiation for 60 minutes. When cooled, the resulting crystals (50 mg, 58%) obtained were filtered, washed with EtOH and dried to afford the title compound.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH3:30])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].ClC1N=C2SC([C:46](NC3C=C(NC(=O)C4C=CC=C(C(C#N)(C)C)C=4)C=CC=3C)=[O:47])=CC2=NC=1.NCCO>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH2:30][CH2:46][OH:47])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: CNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Solvent: NCCO
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(NCCO)nc2s1
Yield: 15 %

Procedure:
Preparation analogous to 96a by using 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (0.061 mmol, 30 mg) and 2-aminoethanol (1.53 mmol, 92 μL). The crude compound was purified by HPLC and the chromatography (0-10 methanol in CH2Cl2) to give N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(2-hydroxyethylamino)thieno[2,3-b]pyrazine-6-carboxamide 96h (5 mg, 15%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.24 (s, 3H), 3.44 (q, J=5.9 Hz and 5.1 Hz, 2H), 3.59 (q, J=5.9 Hz and 5.1 Hz, 2H), 4.83 (t, J=5.1 Hz, 1H), 7.28 (d, J=8.6 Hz, 1H), 7.60 (m, 2H), 7.75 (m, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.89 (m, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.17 (s, 1H), 8.25 (s, 1H), 10.08 (s, 1H), 10.34 (s, 1H). (m/z)=516 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][CH2:16][OH:17])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.O>C(#N)C>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][CH2:16][OH:17])=[CH:7][CH:8]=1)=[O:26]
Reactant: CSc1ccc(-c2oncc2CCCO)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC#N
Solvent: O
Product: CS(=O)c1ccc(-c2oncc2CCCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
To a solution of 3-[5-(4-methylthiophenyl)-4-isoxazolyl]propan-1-ol (900 mg) in acetonitrile (20 ml) was gradually added m-chloroperbenzoic acid (750 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and crystals (390 mg, yield 41%) of 3-[5-(4-methylsulfinylphenyl)-4-isoxazolyl]propan-1-ol were obtained from a fraction eluted with acetone-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-diethyl ether to give a colorless prism. melting point: 73–74° C.
Reaction SMILES: C(=N[NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][N:20]=[CH:21]2)(C1C=CC=CC=1)C1C=CC=CC=1.[C:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)[CH3:27].CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[C:29]1([C:26]2[NH:15][C:16]3=[C:17]4[C:22](=[CH:23][CH:24]=[C:25]3[CH:27]=2)[CH:21]=[N:20][CH:19]=[CH:18]4)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)c1ccccc1
Reactant: c1ccc(C(=NNc2cccc3cnccc23)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: c1ccc(-c2cc3ccc4cnccc4c3[nH]2)cc1
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of N-benzhydrylidene-N′-isoquinolin-5-yl-hydrazine 4A (1.4 mmol) and acetophenone (2.1 mmol) in EtOH (7 mL), pTSA (5.6 mmol) was added and the mixture was submitted to microwaves at 120° C. for 1 h. The solvent was removed, the residue was dissolved in DCM and washed with aq saturated NaHCO3. The organic layer was dried (Na2SO4) and concentrated. The crude material was then purified by chromatography on silica gel (eluant: hexane/AcOEt 4:6) affording the title compound (58% yield). ESI (+) MS: m/z 245 (MH+). 1H NMR (500 MHz): 7.16 (d, J=2.20, 1H), 7.37 (t, J=7.45, 1H), 7.53 (t, J=7.81, 2H), 7.63 (d, J=8.79, 1H), 7.83 (d, J=8.79, 1H), 8.00 (d, J=7.32, 2H), 8.44 (d, J=5.62, 1H), 8.56 (d, J=5.62, 1H), 9.22 (bs, 1H), 12.40 (bs, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.[CH3:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(CC)CC>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CCOC(C)=O.C(O)CC>[CH2:10]([O:9][P:8]([C:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:16])[CH:22]=2)[CH:7]=[CH:6][CH:5]=1)([O:12][CH2:13][CH3:14])=[O:15])[CH3:11]
Reactant: CCOP(=O)(OCC)c1cccc(I)c1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1cccc(-c2cccc(C)c2)c1
Reaction time: 18 h

Procedure:
To a compound of Step 1 (0.200 g, 0.588 mmol) in toluene (5 mL)—H2O (1.5 mL)-n-propanol (5 mL) were added 3-methyl phenyl boronic acid (0.158 g, 1.17 mmol), tris(dibenzylidene acetone)dipalladium (0.030 g), triphenylphosphine (0.123 g) and Et2NH (0.083 mL). After a period of 18 h at 80° C., the reaction mixture was partionned between EtOAc and H2O. The organic phase was separated, dried over Na2SO4, filtered and evaporated under reduced pressure. The title compound was obtained after flash chromatography (0.122 g).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl:17][CH2:18][C:19](Cl)=[O:20]>O>[CH:1]([N:4]([CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[C:19](=[O:20])[CH2:18][Cl:17])([CH3:3])[CH3:2]
Reactant: CC(C)NCC1OCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)N(CC1OCCO1)C(=O)CCl

Procedure:
N-Isopropyl-N-(1,3-dioxolan-2-ylmethyl)amine (9.5 grams) benzene (100 ml), water (100 ml) and sodium carbonate (10 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (5 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-isopropyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C@H:4]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.[NH2:19][CH:20]([CH2:32][CH2:33][CH3:34])[C@@H:21]([C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)[OH:22]>>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[C:21]([C@@H:20]([NH:19][C:5](=[O:7])[C@@H:4]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[CH2:3][C:2]([CH3:1])([CH3:18])[CH3:17])[CH2:32][CH2:33][CH3:34])=[O:22]
Reactant: CC(C)(C)C[C@H](CC(=O)N1CCOCC1)C(=O)O
Reactant: CCCC(N)[C@H](O)c1nc2ccccc2o1
Product: CCC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CC(C)(C)C)C(=O)c1nc2ccccc2o1

Procedure:
It is similarly prepared according to general procedure given for example 10 above but using (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid and (S)-2-Amino-1-benzoxazol-2-yl-pentan-1-ol.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[CH:16]=[C:15]4[O:20][CH2:21][O:22][C:14]4=[CH:13][C:12]=3[C:11]2=[O:23])[CH2:4][CH2:3]1.Cl.Cl[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[CH:16]=[C:15]4[O:20][CH2:21][O:22][C:14]4=[CH:13][C:12]=3[C:11]2=[O:23])[CH2:4][CH2:3]1
Reactant: O=C1c2cc3c(cc2C(=O)N1CCC1CCNCC1)OCO3
Reactant: ClCc1ccccn1
Agent: Cl
Product: O=C1c2cc3c(cc2C(=O)N1CCC1CCN(Cc2ccccn2)CC1)OCO3

Procedure:
Compound I-36 was prepared according to the method in example 3, using 6-[2-(4-piperidyl)ethyl]-[1,3]dioxolo[4,5-f]isoindole-5,7-dione hydrochloride (compound II-1) and 2-chloromethylpyridine hydrochloride as the raw materials: 1H NMR (DMSO-d6): δ 1.12-1.19 (m, 3H), 1.48 (q, 2H, J=6.1 Hz), 1.67 (d, 2H, J=9.4 Hz), 1.94 (t, 2H, J=10.3 Hz), 2.76 (d, 2H, J=11.2 Hz), 3.54 (m, 4H), 6.27 (s, 2H), 7.24 (dd, 1H, J=6.8, 5.4 Hz), 7.38 (s, 2H), 7.42 (d, 1H, J=7.8 Hz), 7.74 (td, 1H, J=7.7, 1.4 Hz), 8.64 (d, 1H, J=4.2 Hz): m/z 394 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[F:20][C:21]([F:32])([F:33])[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: O=C(O)c1cccc(COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)c1

Procedure:
3-(4′-Trifluoromethoxy-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure 1 from 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 4-(trifluoromethoxy)benzeneboronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=389.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:7]=[N:6][C:5]=2[NH:4][C:3]1=O.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:3]1[N:2]([CH3:1])[C:10](=[O:11])[C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:7]=[N:6][C:5]=2[N:4]=1
Reactant: Cn1c(=O)[nH]c2ncn(Cc3ccccc3)c2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1c(Cl)nc2ncn(Cc3ccccc3)c2c1=O

Procedure:
Heat 1-methyl-7-(phenylmethyl)purine-2,6-dione (8.0 g=31 mmol)in POCl3 (80 ml) at reflux 7 hr. Concentrate in vacuo, partition EtOAc-ice water, wash with water, dry and concentrate. Chromatograph on silica with 98:2 CH2Cl2 /MeOH to obtain the title compound as a foam, FAB MS: M+1=275.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])=[CH:4][CH:3]=1.[C:16]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34](=O)[CH3:35])[CH:29]=2)=[O:26])[CH2:21][CH2:20]1)(=[O:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(O)(=O)C.[Cl-].C(O[Ti+](OC(C)C)OC(C)C)(C)C>[C:16]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([NH:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH3:35])[CH:29]=2)=[O:26])[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1cccc(NC(=O)C2CCN(C(C)=O)CC2)c1
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(C)O[Ti+](OC(C)C)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)Nc2cccc(C(C)Nc3ccccc3Oc3ccc(Cl)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.6 %

Procedure:
2-(4-Chlorophenoxy)aniline (137 mg, 0.6237 mmol, 1.1 eq) and 1-acetyl-N-(3-acetylphenyl)piperidine-4-carboxamide (160 mg, 0.5549 mmol, 1 eq) were stirred in dry dichloromethane (DCM) at room temperature for 10 min. Tri-isopropoxytitanium chloride (295 μL, 1.2351 mmol, 2.2 eq) was added to the reaction mixture which was stirred at room temperature for an additional 10 min. Sodium triacetoxyborohydride (590 mg, 2.7838 mmol, 5 eq) and acetic acid (3 drops) were added to the reaction mixture which was stirred at room temperature for 16 h. The reaction mixture was then poured onto a solution of saturated aqueous sodium bicarbonate (100 mL) and extracted with DCM (80 mL). The organic layer was washed with brine (100 mL), dried over MgSO4, filtered and concentrated to give the crude as a yellow oil. Purification of the crude by flash chromatography (ISCO) eluting with a gradient [from 100% petroleum ether (PE) to 100% EtOAc] gave the title compound (48 mg, 18%) as a clear oil.