Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([O:10][CH2:11][CH:12]=[CH2:13])[CH:6]([OH:9])[CH:7]=[CH2:8])[CH3:2].[CH3:15][C:16](OC(C)=O)=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCN(CC)CC.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([O:10][CH2:11][CH:12]=[CH2:13])[CH:6]([O:9][C:16](=[O:17])[CH3:15])[CH:7]=[CH2:8])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCOC(C(=O)OCC)C(O)C=C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(C(=O)OCC)C(C=C)OC(C)=O
Temperature: 25 °C

Procedure:
To a solution of 2-allyloxy-3-hydroxy-pent-4-enoic acid ethyl ester (100 mg, 0.5 mmol) and DMAP (30 mg, 0.25 mmol) in CH2Cl2-Et3N (9:1, 10 mL) was added Ac2O (76 mg, 0.75 mmol). The resulting solution was stirred at ambient temperature for 1H. The solution was diluted with CH2Cl2 (40 mL), washed with H2O (20 mL×2), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography with 20% EtOAc-hexane.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.CCCCCC.[C:39]([O:43][C:44]([N:46]1[CH2:50][CH2:49][CH:48]([C:51](=[O:56])N(OC)C)[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[C:39]([O:43][C:44]([N:46]1[CH2:50][CH2:49][CH:48]([C:51]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[N:9]=3)[NH:4][CH:3]=2)=[O:56])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4CCN(C(=O)OC(C)(C)C)C4)c3n2)cc(OC)c1OC
Reaction time: 0.01 h

Procedure:
7-Iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine 0.057 gm, 0.1 mM was placed in an oven dried flask and 1 ml anhydrous THF was added. The flask was chilled in an Acetone-dry ice slurry and evacuated and refilled 3 times with nitrogen. Via syringe 0.061 ml of 2.13M Buli in hexane solution (0.13 mM, 1.3 eq) was added and the now yellow mixture was stirred for 30 seconds then 3-(Methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, 0.052 gm, 0.2 mM, 2 eq.) in a minimal amount of THF was added by syringe. The mixture was stirred for 30 minutes, removed from the dry ice-acetone bath and immediately quenched with a saturated aqueous ammonium chloride solution. The mixture was extracted two times with ethyl acetate and the organic extracts dried over magnesium sulfate. After filtering and concentrating, the oil was redissolved in THF and 0.2 ml of 1M Tetrabutylammonium Fluoride in THF added. After 5 minutes the mixture was concentrated and purified on a preparative thin-layer chromatography plate (Ethylacetate/hexane) to give 3-[2-(3,4,5-Trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-pyrrolidine-1-carboxylic acid tert-butyl ester. The 3-[2-(3,4,5-Trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 3 ml of dichloromethane and 0.4 ml trifluoroacetic acid was added and stirred overnight. The solution was concentrated and the solid dried overnight at 2 torr in a 60° C. vacuum oven to give 0.012 gm of Pyrrolidin-3-yl-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone trifluoroacetate salt. (M+H)+=383.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCCCOC(c1ccccc1)c1ccccc1
Reactant: C1CNCCN1
Product: c1ccc(C(OCCCCCCN2CCNCC2)c2ccccc2)cc1
Yield: 94 %

Procedure:
Using 6-(dipenylmethoxy)hexyl chloride and piperazine, the procedure of Reference Example 16 was otherwise repeated to provide the title compound.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([C@H:4]([C@@H:6]([C@@H:8](CO)[OH:9])[OH:7])[OH:5])[OH:3]>O.C(O)C>[CH2:1]([OH:12])[C@@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Solvent: O
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Yield: 119.7 %

Procedure:
The procedure of Example 1 was repeated except that 300 mg of mannitol was dissolved in a mixture of 10 mg of water and 10 mg of ethanol, the solution was subjected to wet granulation, and the resulting wet granules were dried and used as the sugar alcohol, not 300 mg of xylitol, to obtain an inventive rapidly disintegrating formulation tablet.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH:19]=O)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: NCC1CCNCC1
Reactant: COC(=O)c1cc(C=O)cc(-c2cccc(C#N)c2)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(CNCC2CCNCC2)cc(-c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.8 %

Procedure:
In 20 ml of toluene, were added 1.0 g of the compound obtained in Example 11 and 500 mg of 4-aminomethylpiperidine. The resulting mixture was refluxed using a Dean-Stark device under heating for 2 hours to remove the produced water. The solvent was then evaporated, and 20 ml of anhydrous methanol was added to dissolve the residue. To the obtained solution, was added 100 mg of 5% palladium-carbon. The mixture was stirred at room temperature under hydrogen atmosphere. After 4 hours, 200 mg of the 5% palladium-carbon was further added, and the reaction mixture was stirred for another 65 hours. The catalyst was separated by filtration, and the reaction mixture was concentrated. The resulting concentrate was then dissolved in a mixed solvent of water-dichloromethane, and the aqueous layer was separated and concentrated to afford 0.82 g (60%) of the title compound as a light-yellow oily substance.
Reaction SMILES: NN.[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:21][O:22][N:23]3C(=O)C4C(=CC=CC=4)C3=O)[N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:12]=2[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:23][O:22][CH2:21][C:15]1[N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:12]2[C:11]3[N:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[C:4]([NH2:3])[C:13]=2[N:14]=1
Reactant: CC(C)Cn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3cccnc3c21
Agent: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Cn1c(CON)nc2c(N)nc3cccnc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
Anhydrous hydrazine (0.640 mL, 20.2 mmol) was added to a suspension of 2-{[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methoxy}-1H-isoindole-1,3(2H)-dione (2.81 g, 6.75 mmol) in ethanol (40 mL). Gradually, a solution formed from which a solid began to precipitate. The reaction mixture was stirred overnight at room temperature, then was concentrated under reduced pressure. The residue was triturated with 1 M aqueous hydrochloric acid (50 mL). The mixture was sonicated and the solid was isolated by filtration. The filtrate was adjusted to pH 8 with solid sodium carbonate and extracted with dichloromethane (3×25 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to afford a yellow solid. The solid was triturated with methanol to afford 0.863 g of 2-[(aminooxy)methyl]-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=C)=[CH:15][CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([NH2:23])=[O:22])=[CH:9]2)=[CH:4][CH:3]=1.CC(C)=[O:26].O.I([O-])(=O)(=O)=O.[Na+]>CCOC(C)=O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[O:26])=[CH:15][CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([NH2:23])=[O:22])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: C=Cc1ccc2c(c1)c(=O)c(C(N)=O)cn2-c1ccc(F)cc1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C=O)cc2c1=O
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of compound F (385 mg, 1.25 mmol) in 3:1 acetone/water (8 mL) was added N-oxide-4-methylmorpholine (220 mg, 1.87 mmol) and osmium tetroxide (254 μL, 0.025 mmol). After the reaction stirred for one hour, sodium periodate (294 mg, 1.37 mmol) was added. After another two hours, the reaction was diluted with EtOAc and washed well with a 10% NaS2O3 solution. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 365 mg (94%) of the title compound that was used without further purification. ES-MS [M+1]+: 311.2.
Reaction SMILES: [Na].Cl[C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4]=1[C:5]([CH3:18])=[CH:6][CH:7]=[N:8]2.N1C=CC=CC=1.[CH3:25][OH:26]>>[CH3:25][O:26][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4]=1[C:5]([CH3:18])=[CH:6][CH:7]=[N:8]2
Reactant: CO
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1Cl
Agent: [Na]
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OC

Procedure:
To a solution of sodium metal (4.8 g, 0.2 g. atom) in methanol (300 ml) were added 50.6 g (0.2 mole) of 5-chloro-6-methoxy-4-methyl-8-nitroquinoline and 70 ml of pyridine. The mixture was stirred under reflux for 48 hr, treated with carbon and filtered hot. The residue was washed with hot methanol and the filtrate and washings were combined (total, 600 ml). On standing, 15 g of 5,6-dimethoxy-4-methyl-8-nitroquinoline, separated, mp 120°-124°. The filtrate was concentrated to 200 ml and cooled overnight to give an additional 15 g of 5,6-dimethoxy-4-methyl-8-nitroquinoline. Dilution of this filtrate with 6 liters of water provided 7 g of product for a total crude yield of 37 g. Crystallization from methanol (carbon) gave 34 g (68%) of 5,6-dimethoxy-4-methyl-8-nitroquinoline, mp 123°-125°. The same compound (m.p. and mixed m.p. 123°-125°) resulted when a Skraup reaction was performed on 4-amino-5-nitroveratrole and methyl vinyl ketone.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][N:5]1[C:11](=[O:12])[C@H:10]([OH:13])[C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[S:8][C:7]2[C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=[CH:25][C:6]1=2.N1C=CC=CC=1.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([O:13][C@@H:10]1[C@H:9]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[S:8][C:7]2[C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:30])[C:11]1=[O:12])(=[O:39])[CH3:38]
Reactant: COC(=O)c1cccc2c1S[C@@H](c1ccc(OC)cc1)[C@@H](O)C(=O)N2CCN(C)C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc2c1S[C@@H](c1ccc(OC)cc1)[C@@H](OC(C)=O)C(=O)N2CCN(C)C
Temperature: 22 °C
Reaction time: 3 h

Procedure:
To a solution of 19 mg (0.045 mmol) of (+/−)-(2S,3S)-methyl 5-(2-(dimethylamino)ethyl)-3-hydroxy-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-9-carboxylate in 0.5 mL of DCM was added 22 μL (0.27 mmol) of pyridine and 4 μL (0.06 mmol) of acetyl chloride. The reaction was stirred at 22° C. for 3 hours. The reaction mixture was diluted with DCM, washed sequentially with 1 M Na2CO3 and water, dried (Na2SO4), and evaporated. The residue was purified by flash chromatography on silica gel, eluting with DCM then gradually increasing to 3% methanol/DCM to give 1a. MS found M+H=473. The hydrochloride salt of 1a was recrystallized from ethyl acetate; mp 169-172° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1C=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(CO)o2)c1
Agent: O=Cc1oc(CNS(=O)(=O)c2ccccc2)cc(=O)c1OCc1ccccc1
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C=O)o2)c1
Yield: 75.3 %

Procedure:
N-(5-Benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (11-04) (1.8 g, 75.28%) was synthesized as a white solid from N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (10-04) (2.4 g, 5.78 mmol) following the procedure described for N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (11-01).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:12]([C:13](O)=O)=C[NH:10][C:7]2=N[CH:9]=1)([O-])=O.C[N:17](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.N1C2C(=CC=CN=2)C=C1>CN(C=O)C>[NH:17]1[C:12]2[C:6](=[CH:5][CH:4]=[CH:9][CH:13]=2)[CH:7]=[N:10]1
Reactant: O=C(O)c1c[nH]c2ncc([N+](=O)[O-])cc12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: c1cnc2[nH]ccc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To the resin (1.5 g, 0.77 mmol/g, 1.16 mmol) of example 7 in anhydrous DMF (15 ml), it was added 5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (0.359 g, 1.73 mmol), TBTU (0.556 g, 1.73 mmol) and DIPEA (0.44 g, 3.48 mmol). The reaction mixture was shaken at room temperature for 20 hours and then the resin was isolated by filtration. The resin was washed sequentially with DMF (25 ml), DCM (25 ml), DMF (25 ml), DCM (25 ml), MeOH (25 ml), DCM (25 ml), MeOH (25 ml), DCM (25 ml), MeOH (25 ml), TBME (25 ml×2) and dried in vacuo to give the resin bound 7-azaindole (1.70 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24](O)=[O:25]>>[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:25]
Reactant: Cc1ccsc1C(=O)O
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: Cc1ccsc1C(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 12 mg (0.084 mMol) 3-methylthiophene-2-carboxylic acid, the title compound was recovered as a beige solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:11][CH:10]=1.CCN(CC)CC.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:18]=[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=1
Reactant: Nc1ccc(CCC(=O)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CCC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (2.45 mL, 26 mmol) was added to a solution of 3-(4-amino-phenyl)-1-phenyl-propan-1-one from Example X (4.5 g, 20 mmol), NEt3 (3.1 mL, 22.2 mmol), and a crystal of DMAP in CH2Cl2 (50 mL). The reaction mixture was stirred overnight at room temperature, then poured onto 1N HCl. The product was partitioned between CH2Cl2 and H2O, and the organic phase was dried (MgSO4) and concentrated to give the title compound. 1H NMR (CDCl3) δ 2.16 (s, 3 H), 3.03 (t, 2 H), 3.28 (t, 2 H), 7.20 (d, 2 H), 7.37-7.60 (m, 6 H), 7.94 (d, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](O)=[O:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](=[O:18])[NH:28][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: NCCc1ccccc1
Reactant: O=C(O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(NCCc1ccccc1)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 83.8 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxy-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.92 mmol) and phenethylamine (121 mg, 1.0 mmol) to give 330 mg of the title compound(84%): mp>250° C.; 1H NMR (270 MHz, DMSO-d6) δ12.12 (s, 1H), 8.21 (t, 1H, J=5.6 Hz), 7.09~7.39 (m, 7H), 5.07 (m, 1H), 3.24~3.33 (m, 2H), 2.64~2.73 (m, 3H), 2.25~2.32 (m, 2H), 1.80~1.95 (m, 1H).
Reaction SMILES: [C:1]([CH:8]([O:23][NH2:24])[CH:9]([F:22])[CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].[CH3:27]I>C(O)C>[C:1]([CH:8]([O:23][NH2:24])[CH:9]([F:22])[CH2:10][N:11]([CH3:27])[S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:13])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)NCC(F)C(ON)C(=O)OC(C)(C)C)cc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(C)CC(F)C(ON)C(=O)OC(C)(C)C)cc1

Procedure:
0.54 g (1.5 mmol) of N-(3-BOC-aminoxy-2-fluoropropyl)-4-toluenesulfonamide are dissolved in 10 ml of ethanol and 1.5 ml of 1N sodium hydroxide solution and, after the addition of 0.21 g (1.5 mmol) of methyl iodide, maintained at 70° for 10 hours in a bomb tube. After cooling, the reaction mixture is concentrated by evaporation and the residue is taken up in ethyl acetate. The resulting solution is washed with water and dried over magnesium sulfate, yielding, after evaporation of the solvent, starting compound c.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][CH:10]([OH:13])[CH2:11][NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:7]2[O:8][CH2:9][CH:10]([O:13][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24])[CH2:11][NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CNc2cccc(Br)c2OC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CNc2cccc(Br)c2OC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of 9-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ol (0.456 g, 1.868 mmol) and imidazole (0.280 g, 4.11 mmol) in DMF (5.0 mL) was added TBSCl (0.619 g, 4.11 mmol). The reaction was stirred at room temperature for 18 h. The mixture was diluted with a solution of saturated sodium bicarbonate (15 ml) and extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (648 mg, 1.718 mmol, 92% yield) as clear oil. LCMS, [M+H]+=360.1. 1H NMR (400 MHz, CDCl3) δ 6.99 (dd, J=7.8, 1.4 Hz, 1H), 6.69 (t, J=7.9 Hz, 1H), 6.57 (dd, J=7.9, 1.5 Hz, 1H), 4.39 (dd, J=11.9, 4.8 Hz, 1H), 4.19 (tt, J=6.5, 4.7 Hz, 1H), 3.94 (dd, J=11.9, 6.8 Hz, 1H), 3.67 (br. s., 1H), 3.54 (dt, J=13.2, 4.1 Hz, 1H), 3.17 (dd, J=12.3, 5.5 Hz, 1H), 0.93-0.90 (m, 9H), 0.11 (s, 6H).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([OH:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].CC1(C)N([O])C(C)(C)CCC1.C([O-])(=[O:26])C.C([O-])(=O)C.C1([I+2])C=CC=CC=1.Cl>O1CCOCC1.O>[O:12]=[C:3]([CH:2]=[CH2:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:26])=[O:11]
Reactant: CC(=O)[O-]
Reactant: C=CC(O)CCCCCCCO
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Agent: [I+2]c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: C=CC(=O)CCCCCCC(=O)O

Procedure:
To a solution of 1-decene-3,10-diol (920 mg, 5.34 mmol, 1.00 eq.) in 1,4-dioxane (15.0 mL) and H2O (10.0 mL), were added a catalytic amount of TEMPO and phenyliodine diacetate (2.06 g, 6.41 mmol, 1.20 eq.) at room temperature. The mixture was allowed to react at the same temperature for 20 hours, and then the reaction solution was poured into 1 M aqueous hydrochloric acid solution and a saturated salt solution. The organic phase was extracted with chloroform. Then, the resulting organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol=97:3) to obtain 8-oxo-9-decenoic acid as shown below (915 mg, 4.97 mmol, 93%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([N:26]1[CH2:31][CH2:30][NH:29][C@H:28]([CH3:32])[CH2:27]1)(OC(C)(C)C)=O.[ClH:33]>O1CCOCC1>[ClH:33].[CH3:32][C@@H:28]1[CH2:27][NH:26][CH2:31][CH2:30][N:29]1[C:16]([C:14]1[S:15][C:11]([C:3]2[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(C(=O)N3CCNC[C@H]3C)s2)noc1C(F)(F)F
Reaction time: 2 h
Yield: 86 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-N-Boc-2-(R)-methyl-piperazine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford intermediate N-Boc protected product as a colorless solid (106 mg, 92%). The Boc-protected intermediate was dissolved in a 4 N solution of hydrogen chloride in 1,4,-dioxane (2 mL) and stirred for 2 hr, after which time the reaction mixture was evaporated to approximately ¼ volume and diluted with ethyl ether (4 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (85 mg, 86% overall). 1H NMR (D2O) 1.27 (d, J=7.5, 3 H), 2.02 (s, 3 H), 3.04 (dt, J=12.7, 3.1, 1 H), 3.12-3.18 (m, 2 H), 3.30-3.50 m (m, 2 H), 4.21 (d, J=14.5, 1 H), 7.23 (s, 2 H). 19F NMR −64.1. LC/MS 4.50 min, [M+1]+ 360.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14]C2CCCCO2)=[O:12])[C:4](=[O:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)=[CH:37][CH:36]=2)O1>>[OH:14][NH:13][C:11](=[O:12])[C:10]([CH3:25])([S:21]([CH3:24])(=[O:22])=[O:23])[CH2:9][CH2:8][N:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=3)=[CH:39][CH:40]=2)=[CH:3][C:4]1=[O:26]
Reactant: CC1(C)OB(c2ccc(-c3ccncc3)cc2)OC1(C)C
Reactant: CC(CCn1ccc(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Product: CC(CCn1ccc(-c2ccc(-c3ccncc3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O

Procedure:
(+/−)-4-(4-Iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, which may be prepared as in Preparation 2A and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine were converted to the title product following the general procedure outlined for (+/−)-4-[4-(1-benzofuran-2-yl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide in Example 33, Step A. The title compound was obtained as a white solid (161 mg, 61%) LC-MS m/z 526.7 (M+1).