Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@:2]1([CH3:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8]I)[O:4][C@H:3]1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17].C[O-].[Na+]>CO>[F:1][C@:2]1([CH3:18])[C@H:6]([OH:7])[C:5](=[CH2:8])[O:4][C@H:3]1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17]
Reactant: C[C@@]1(F)[C@H](O)[C@@H](CI)O[C@H]1n1ccc(=O)[nH]c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=C1O[C@@H](n2ccc(=O)[nH]c2=O)[C@](C)(F)[C@@H]1O
Temperature: 65 °C
Reaction time: 14 h
Yield: 61.9 %

Procedure:
Chiral 1-((2R,3R,4R,5S)-3-fluoro-4-hydroxy-5-(iodomethyl)-3-methyl-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (8.2 g, 22 mmol) was dissolved in MeOH (100 mL) and NaOMe (3.73 g, 69 mmol) was added into it under nitrogen atmosphere, after addition, the mixture was heated to 65° C. and stirred under nitrogen atmosphere for 14 hrs, TLC showed that the SM was consumed, then the mixture cooled to r.t., IR-120 (H) ion exchange resin was added into it to adjust the pH to 8, filtered and removed solvent by reduced pressure, the crude product was purified by silica gel chromatography column (DCM:MeOH=15:1) to afford the title compound as a white solid (3.3 g, 59%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=O)=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])[CH:2]([CH3:4])[CH3:3].S(O)(O)(=O)=O.[NH2:23][C:24]1[C:29]([NH2:30])=[C:28]([NH2:31])[N:27]=[CH:26][N:25]=1.O>O1CCOCC1.[OH-].[Na+]>[NH2:31][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[C:29]=1[NH:30][C:10]([C:9]1[CH:13]=[CH:14][C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=1)=[N:23]2
Reactant: CC(C)COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: Nc1ncnc(N)c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)COc1ccc(-c2nc3ncnc(N)c3[nH]2)cc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 21 %

Procedure:
A solution of 4-isobutoxy-3-nitrobenzoyl chloride (538 mg, 2.09 mmol) in 1,4-dioxane (2 mL) was dropwise added to a suspension of 4,5,6-triaminopyrimidine sulfate (466 mg, 2.09 mmol) in aqueous 1M sodium hydroxide (4.18 30 mL) under cooling with ice. The resulting mixture was stirred for 4 hours at the same temperature. Water (12 mL) was added to the reaction mixture. The precipitated solid product was collected by filtration, dried in air, and subjected to silica gel column chromatography. The elute using chloroform/methanol (10/1) gave 144 mg (yield 20%) of the desired compound in the form of a yellow powdery product.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[F:5][C:6]1[CH:7]=[C:8](Br)[CH:9]=[C:10]([F:12])[CH:11]=1.[Mg].O>O1CCCC1>[CH2:3]([C:8]1[CH:7]=[C:6]([F:5])[CH:11]=[C:10]([F:12])[CH:9]=1)[CH:2]=[CH2:1]
Reactant: Fc1cc(F)cc(Br)c1
Reactant: C=CCBr
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: C=CCc1cc(F)cc(F)c1
Temperature: 20 °C

Procedure:
A solution of allyl bromide (2.5 g) in dry tetrahydrofuran (10 ml) was added dropwise with stirring to 3,5-difluorobromobenzene (4.0 g) with magnesium (0.5 g) in dry tetrahydrofuran) in dry tetrahydrofuran (40 ml), whilst maintaining the temperature of the mixture at about 20° C. When the addition was complete the mixture was allowed to warm to the ambient temperature (ca. 25° C.). After a period of 18 hours the mixture was poured into water (100 ml) and the resultant mixture extracted with diethyl ether, the extract washed with water, dried over anhydrous magnesium sulphate and the ether removed by distillation at atmospheric pressure. The residual oil was purified by distillation at atmospheric pressure to yield allyl-3,5-difluorobenzene (b.p. 154°-155°) as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:12]2C(=O)OC(C)(C)[O:14][C:13]2=[O:21])[C:9]([CH3:11])=[CH2:10])[CH:5]=[CH:6][CH:7]=1.OC1C=C(C(CC=C)CC(O)=O)C=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]([CH3:11])=[CH2:10])[CH2:12][C:13]([OH:21])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C(c1cccc(O)c1)C1C(=O)OC(C)(C)OC1=O
Agent: C=CCC(CC(=O)O)c1cccc(O)c1
Product: C=C(C)C(CC(=O)O)c1cccc(O)c1
Yield: 101.8 %

Procedure:
Compound 48.1 (0.88 g, 3.0 mmol) was hydrolyzed according to the method described for preparation of 43.2 to afford 48.2 (0.63 g).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].C[OH:8].[CH2:9]([S:17][C:18]1[N:23]=[N:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:41])([F:40])[F:39])=[O:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[C:11]1([CH2:10][CH2:9][S:17]([C:18]2[N:23]=[N:22][C:21]([N:24]3[CH2:25][CH2:26][N:27]([C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:40])[F:39])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)=[O:8])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(SCCc3ccccc3)nn2)CC1
Reactant: CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(S(=O)CCc3ccccc3)nn2)CC1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To an ice-cold solution of sodium periodate (0.025 g, 0.12 mmol) in 1:1 mixture of water and methanol was added [4-(6-phenethylsulfanylpyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone. The reaction mixture was stirred at room temperature over night, diluted with water and then extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous MgSO4 and then concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (41 mg, 69.2%). 1H NMR (400 MHz, CDCl3) δ 7.86, 7.75, 7.63-7.66, 7.56-7.59, 7.37, 7.25-7.28, 7.21-7.17, 7.07-7.09, 4.04-4.10, 3.83-3.91, 3.70-3.80, 3.45-3.35, 3.26-3.30, 3.2-3.15.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([C:43]2([CH3:50])[CH2:47][CH2:46][N:45]([CH3:48])[C:44]2=[O:49])=[N:41][CH:42]=1>>[CH3:48][N:45]1[CH2:46][CH2:47][C:43]([C:40]2[N:41]=[CH:42][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:38][CH:39]=2)([CH3:50])[C:44]1=[O:49]
Reactant: CN1CCC(C)(c2ccc(Br)cn2)C1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(C)CCN(C)C3=O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 65 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 3-(5-bromo-pyridin-2-yl)-1,3-dimethyl-pyrrolidin-2-one following a procedure analogous to that described in Example 1. Yield: 65% of theory; LC (method 3): tR=3.06 min; Mass spectrum (ESI+): m/z=542 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]1([C@H:19]([N:21]2[N:25]=[N:24][CH:23]=[N:22]2)[CH3:20])[CH2:18][O:17]1.O>CN(C)C=O.C(OCC)(=O)C>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:17])([C@H:19]([N:21]1[N:25]=[N:24][CH:23]=[N:22]1)[CH3:20])[CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[C@@H](n1ncnn1)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](n1ncnn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.9 %

Procedure:
1H-1,2,4-Triazole (48 mg) was added to a dispersion of 60% sodium hydride in oil (27 mg) in dimethylformamide (1.1 ml) under ice-cooling and the resulting mixture was stirred for 10 minutes at room temperature. After addition of a solution of (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(2H-tetrazol-2-yl)ethyl]oxirane (89 mg) in dimethylformamide (0.7 ml), the mixture was heated for 5 hours at 50° C. and cooled. Cold water (10 ml) and ethyl acetate (20 ml) were added to the reaction mixture. The separated aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated saline, dried over anhydrous magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1:1→2:1→ethyl acetate) to give the title compound (Compound 4, 60 mg, 53%) as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[C:3]([OH:21])=[C:4]([C:14]([OH:20])=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)[C:5](OC1C=CC=CC=1)=[O:6].[NH2:22]C1C=CC(C(C2C=CC(OC)=CC=2)C#N)=C(C(F)(F)F)C=1.ClC1C=CC(Cl)=CC=1Cl>>[OH:21][C:3]1[CH:2]=[CH:16][C:15]([N+:17]([O-:19])=[O:18])=[C:14]([OH:20])[C:4]=1[C:5]([NH2:22])=[O:6]
Reactant: COc1ccc(C(C#N)c2ccc(N)cc2C(F)(F)F)cc1
Reactant: O=C(Oc1ccccc1)c1c(O)c(Cl)cc([N+](=O)[O-])c1O
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: NC(=O)c1c(O)ccc([N+](=O)[O-])c1O
Temperature: 190 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3 parts of phenyl 3-chloro-2,6-dihydroxy-5-nitrobenzoate, 3 parts of 4-amino-α-(4-methoxyphenyl)-2-(trifluoromethyl)benzeneacetonitrile and 30 parts of 1,2,4-trichlorobenzene is stirred for 10 minutes at 190° C. The reaction mixture is cooled and poured onto 140 parts of petroleumether while stirring. The supernatant phase is decanted and the residue is boiled in methylbenzene and stirred with activated charcoal. The latter is filtered off over hyflo. Petroleumether is added to the filtrate till turbid and the product is allowed to crystallize while stirring. It is filtered off, dried and crystallized from acetonitrile, yielding 4.5 parts of 3-chloro-N-{4-[α-cyano-α-(4-methoxyphenyl)methyl]-3-trifluoromethyl)phenyl}-2,6-dihydroxy-5-nitrobenzamide; mp. 206.4° C.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)#[CH:42].C(N(CC)CC)C>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:42]#[C:41][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: C#Cc1ccccc1
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc2nc(C#Cc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reaction time: 12 h

Procedure:
The solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (35 mg, 0.06 mmol), ethynylbenzene (8 μL, 0.08 mmol), and triethylamine (1 mL) in ethyl acetate (0.5 mL) was degassed with nitrogen. Copper(I) iodide (1 mg) and bis(triphenylphosphine)palladium (II) dichloride (7 mg) were added, and the mixture was stirred for 12 hours. The mixture was diluted with ethyl acetate, washed with water and brine, and dried with sodium sulfate. Concentration and purification by flash column chromatography (silica gel, ethyl acetate/hexanes) gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinolin-6-yl)ethyl pivalate. LCMS-ESI+ (m/z): [M+H]+ calcd for C35H37ClNO3: 554.2. Found: 554.3.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[CH2:8][CH2:7][CH2:6]2.Br.[OH-].[NH4+]>O>[NH:17]1[CH:18]=[C:14]([CH2:13][CH:9]2[CH2:8][CH2:7][CH2:6][C:5]3[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11][C:10]2=3)[N:15]=[CH:16]1
Reactant: COc1ccc2c(c1)CCCC2Cc1c[nH]cn1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Oc1ccc2c(c1)CCCC2Cc1c[nH]cn1

Procedure:
A stirred mixture of 4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-1H-imidazole (220 mg) and 48% hydrobromic acid (11 ml) is heated under reflux for one hour. The cooled reaction mixture is poured into water and is made basic with ammonium hydroxide solution. The product is extracted into ethyl acetate which is washed with water, dried with sodium sulfate and evaporated to dryness. The crude product is converted to its hydrochloride salt in ethyl acetate. The yield is 130 mg, m.p. 200-205° C.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16](Cl)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1)[CH3:30]>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([N:32]2[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:39](=[O:40])[N:31]2[CH2:29][CH3:30])[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCn1[nH]c2ccccc2c1=O
Reactant: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CCn1c(=O)c2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine and 2-ethyl-1H-indazol-3(2 H)-one were reacted to give 472. LCMS m/z: 534.3 (MH+)
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[H-].[Na+].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17]Br>O1CCCC1.CN(C)C=O.CN(C)C=O>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17][O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:10]
Reactant: OCCCCCCCCO
Reactant: Fc1ccc(CBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OCCCCCCCCOCc1ccc(F)c(F)c1
Yield: 46.2 %

Procedure:
A solution of 1,8-octanediol (300 mg, 2.05 mmol) in tetrahydrofuran/N,N-dimethylformamide 2:1 (3 mL) was added dropwise at 0° C. to a suspension of sodium hydride (60% dispersion in mineral oil, 90 mg, 2.3 mmol) in N,N-dimethylformamide (1.5 mL), then after 2 h 3,4-difluorobenzyl bromide (445 mg, 2.15 mmol) was added. After 4 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded 8-(3,4-difluoro-benzyloxy)-octan-1-ol (258 mg, 46%). Colorless oil, m/e=273.3 ([M+H]+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][C@H:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH2:24][CH3:25].O>CN(C=O)C>[CH2:23]([NH:1][C@@H:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][C@H:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:24][CH3:25]
Reactant: CCOC(=O)[C@@H]1CC2(CC[C@H]1N)OCCO2
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN[C@@H]1CCC2(C[C@H]1C(=O)OCC)OCCO2
Temperature: 50 °C
Yield: 96.4 %

Procedure:
Ethyl 8-amino-trans-1,4-dioxaspiro[4.5]decane-7-carboxylate (118.0 g, 0.52 mole) was dissolved in DMF (1 l) and potassium carbonate (107 g, 0.77 mole) and propyl bromide (158.4 g, 1.3 mole) were added. The mixture was heated to 50° C. for three hours, then poured into water, and the hydrogen ion concentration was adjusted to pH 10. The product was extracted with methylene chloride, dried and evaporated to give 136 g of a dark orange oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[CH2:20])=[N:11][N:12]=1>C(O)C.C(O)(=O)C.[Pd]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:30][CH:31]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH3:20])=[N:11][N:12]=1
Reactant: C=Cc1ccccc1-c1nnc(-c2nc(-c3ccc(C(=O)N(C)C)cc3)cnc2N)o1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1ccccc1-c1nnc(-c2nc(-c3ccc(C(=O)N(C)C)cc3)cnc2N)o1
Yield: 31.4 %

Procedure:
A suspension of 4-[5-amino-6-[5-(2-vinylphenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (45 mg, 0.1091 mmol) in a mixture of ethanol (5 mL) and acetic acid (0.5 mL) in the presence of Pd on C, wet, Degussa (116.1 mg, 0.1091 mmol) was hydrogenated at 60 psi overnight using the parr apparatus. The reaction mixture was filtered through a Celite pad and washed with more ethanol (5 mL) and ethyl acetate (5 mL). The filtrate was dried over MgSO4 and filtered and concentrated in vacuo. Purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]. The product fractions were combined and freeze dried to give the product as a yellow solid (14.2 mg, 38% yield); 1H NMR (400 MHz, DMSO) d 1.30 (t, 3H), 2.98 (m, 6H), 3.13 (q, 2H), 7.48-7.55 (m, 4H), 7.62 (m, 1H), 7.78 (br s, 2H), 8.05 (m, 1H), 8.14 (m, 2H) and 8.99 (1H, s) ppm; MS (ES+) 415.27
Reaction SMILES: C(ON=O)(C)(C)C.N[C:9]1[C:21]([Br:22])=[CH:20][C:12]2[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:11]=2[C:10]=1[Br:23].CCOCC>CN(C=O)C>[Br:23][C:10]1[C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[CH:20]=[C:21]([Br:22])[CH:9]=1
Reactant: Nc1c(Br)cc2oc3ccccc3c2c1Br
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Brc1cc(Br)c2c(c1)oc1ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 116.4 %

Procedure:
To a solution of t-butylnitrite (0.89 ml, 7.2 mmol) dissolved in 10 ml of DMF at 50° C. was added dropwise a solution of 2-amino-1,3-dibromodibenzofuran 17 (1.0 g, 2.9 mmol) in 10 ml of DMF with nitrogen evolution. After stirring at 50° C. for 1 hour the reaction was diluted into ether and washed successively with H2O and saturated NaCl. Drying over MgSO4 and evaporation gave 1.1 g of a red solid which was purified by flash chromatography through 100 g of silica gel (20% methylene chloride: hexane) yielding 650 mg (68%) of the title compound as a pale orange solid.
Reaction SMILES: [SH3+].[H-].[Na+].[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH:11]=[O:12].[CH3:13]S(C)=O>>[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH:11]1[CH2:13][O:12]1
Reactant: O=Cc1ccncc1Br
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Agent: [SH3+]
Product: Brc1cnccc1C1CO1
Reaction time: 0.25 h

Procedure:
To a solution of sulfonium salt (7.39 g, 33.6 mmol) in DMSO (40 mL) was added sodium hydride (60% in oil, 1.236 g, 30.9 mmol) at room temperature. After 15 min of stirring, 3-Bromo-pyridine-4-carbaldehyde (930 mg, 5 mmol) in DMSO (20 was added slowly at this temperature. After addition, the resulting mixture was stirred for another 30 min, and was subsequently quenched with brine. The mixture was extracted with ethyl acetate twice. The combined extracts were dried over anhydrous Na2SO4. After filtration and concentration, the title compound was obtained (200 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([I:12])[CH:3]=1.C[N:14](C=O)C>S(Cl)(Cl)=O>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([NH2:14])=[O:7])=[C:4]([I:12])[CH:3]=1
Reactant: Cc1cc(I)c(C(=O)O)cc1C
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1cc(I)c(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
4,5-Dimethyl-2-iodobenzamide (4f) was obtained from 4,5-dimethyl-2-iodobenzoic acid 4c in two steps. To a solution of 2-iodo-4,5-dimethylbenzo ic acid 4c (1.2 g, 4.34 mmol) in thionyl chloride (20 ml) was added a catalytic amount of DMF, and the resulting solution was heated to redox for 2-3 hours. Excess thionyl chloride was removed under reduced pressure, and the crude acid chloride was dissolved in dry THF (10 ml) and transferred to a pressure vessel. After the addition of 38% aqueous ammonium hydroxide (20 ml), the pressure vessel was sealed and the reaction stirred at room temperature for 12 h. The reaction mixture was then concentrated and diluted with water (75 ml). The product was filtered and washed with water followed by washing with hexanes, and drying (in vacuo) to give the amide 4f (75%) as solid. mp 195-197° C., 1H NMR (400 MHz, DMSO-d6): δ 2.15 and 2.16 (2s, 6H), 7.11 (s, 1H), 7.40 (s, 1H), 7.61 (s, 1H), 7.70 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 19.23, 19.48, 90.12, 129.62, 136.92, 140.18, 140.26, 140.91, 171.25; HRMS (m/z): [M+H]+ calcd for C9H11INO, C9H11INO, 275.9880; found, 275.9878.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[N:7]2.[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>C1(C)C=CC=CC=1.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>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH:22]=[CH2:23])[N:7]=1
Reactant: COc1ccccc1CNc1ccc2c(Br)cccc2n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc2nc(NCc3ccccc3OC)ccc12

Procedure:
(5-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (1000 mg, 2.92 mmol) was dissolved in 30 mL toluene. The reaction mixture was evacuated and backfilled with argon for three times to remove oxygen. Vinyltributyltin (952 mg, 3.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (67 mg, 0.058 mmol) were added. The reaction mixture was refluxed overnight and evaporated. The residue was poured into 50 mL acetonitrile and extracted three times with heptane (50 mL each) to remove the tin products. The acetonitrile phase was dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->80:20 gradient). (2-Methoxy-benzyl)-(5-vinyl-quinolin-2-yl)-amine was obtained as a light yellow gum (544 mg, 64%), MS: m/e=291.3 (M+H+).
Reaction SMILES: C([C@H:3]1[CH2:10][CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:11])[O:7]2)=O.[CH:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CCOCC.O.C(O)C>[CH2:20]([O:19][CH:12]([O:16][CH2:17][CH3:18])[C@H:3]1[CH2:10][CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:11])[O:7]2)[CH3:21]
Reactant: O=C[C@H]1CC[C@@H]2OC(=O)C[C@@H]21
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCOC(OCC)[C@H]1CC[C@@H]2OC(=O)C[C@@H]21

Procedure:
4.3 g. of (1S,5R,6S)-6-formyl-2-oxabicyclo-[3,3,0]octan-3-one [see Example 9(a)], 15 ml. of triethyl orthoformate, and 40 mg. of p-toluenesulfonic acid in 15 ml. of absolute ethyl alcohol are agitated for 16 hours at 20° under argon. The mixture is then diluted with ether, shaken in succession with sodium bicarbonate solution and water, dried over magnesium sulfate, and evaporated under vacuum, thus obtaining 4.8 g. of the title compound as an oil which is completely uniform as determined by thin-layer chromatography.