Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:16])([C:13]([NH2:15])=[O:14])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([O:16][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[Cl:17])([C:10]([NH2:12])=[O:11])[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NC(=O)C(O)(C(N)=O)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: NC(=O)C(OC(=O)c1ccccc1Cl)(C(N)=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 33.1 %

Procedure:
26.3 g of 3,4-dichlorophenylhydroxymalonic acid diamide were dissolved in 50 ml of pyridine, and 17.1 g of o-chlorobenzoyl chloride were added at below 30° C. After one hour, the mixture was stirred into cold 1NCl, the precipitate was taken up in ethyl acetate, the mixture was extracted by shaking and the extract was worked up. 26.5 g of crude product remained, and were recrystallised from 400 ml of ethanol. 13 g of pure 3,4-dichlorophenyl-(2-chlorobenzoyloxy)-malonic acid diamide of melting point 220° C. were obtained.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:22][CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[OH:25]>C(Cl)Cl>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([CH:24]2[O:25][C:11](=[O:13])[NH:22][CH2:23]2)=[CH:27][CH:28]=1
Reactant: Cc1ccc(C(O)CN)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C2CNC(=O)O2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Diisopropylethylamine (181 mg, 244 μL, 1.40 mmol) and triphosgene (138 mg, 0.466 mmol) were added successively to a stirred solution of 2-amino-1-(4-methylphenyl)ethanol (35.2 mg, 0.233 mmol) in dry CH2Cl2 (22 mL) at 0° C. under N2. The reaction was stirred at 0° C. for 1 h then concentrated in vacuo to a volume of about 5 mL. The mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-80% EtOAc in hexanes gradient) to afford 5-(4-methylphenyl)-1,3-oxazolidin-2-one. Rf=0.41 (50% EtOAc/hexanes). LCMS calc.=178.08; found=178.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.25 (d, J=7.4 Hz, 2H), 7.19 (d, J=7.4 Hz, 2H), 6.69 (br s, 1H), 5.55 (t, J=7.8 Hz, 1H), 3.93 (t, J=8.6 Hz, 1H), 3.52 (t, J=8.1 Hz, 1H), 2.35 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]3[CH2:18][CH:19]([NH:24][C:25](=O)[CH2:26][CH3:27])[CH2:20][CH2:21][C:22]=3[CH:23]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.B.C1COCC1>C1COCC1>[CH2:25]([NH:24][CH:19]1[CH2:18][C:17]2[N:16]=[CH:15][C:14]([NH:13][S:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:30])([F:29])[F:1])=[CH:9][CH:8]=3)(=[O:12])=[O:11])=[CH:23][C:22]=2[CH2:21][CH2:20]1)[CH2:26][CH3:27]
Reactant: CCC(=O)NC1CCc2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cnc2C1
Agent: B
Solvent: C1CCOC1
Product: CCCNC1CCc2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cnc2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.2 %

Procedure:
To a solution of N-[3-(4-trifluoromethoxy-benzenesulfonylamino)-5,6,7,8-tetrahydroquinolin-7-yl]-propionamide (260 mg, 0.58 mmol) in THF (10 ml) was added dropwise 1M BH3.THF (5.8 ml) and the mixture was stirred at room temperature for 6 h. It was then quenched by careful addition of 1N aqueous HCl (10 ml) and the resulting solution was heated at reflux for 4 h. The solution was next cooled to room temperature, adjusted to pH˜8 with 2 N NaOH solution and diluted with CH2Cl2. Separation of the layers, drying (Na2SO4) of the organic phase and evaporation in vacuo provided the crude material, which was purified by flash column chromatography (CH2Cl2:MeOH, 95:5) to give the title compound (160 mg, 64%) as a white solid.
Reaction SMILES: C([S:4][CH2:5][CH:6]1[CH2:17][N:9]2[CH2:10][CH2:11][CH2:12][CH:13]([C:14]([OH:16])=[O:15])[N:8]2[C:7]1=[O:18])(=O)C.P([O-])([O-])(O)=O.[Na+].[Na+]>Cl>[SH:4][CH2:5][CH:6]1[CH2:17][N:9]2[CH2:10][CH2:11][CH2:12][CH:13]([C:14]([OH:16])=[O:15])[N:8]2[C:7]1=[O:18]
Reactant: CC(=O)SCC1CN2CCCC(C(=O)O)N2C1=O
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Product: O=C(O)C1CCCN2CC(CS)C(=O)N12
Yield: 72.3 %

Procedure:
1.8 g of 2-acetylthiomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid were heated at 95° C. for 1.5 hours in 2 M hydrochloric acid. The mixture was cooled, the pH was adjusted to 3 by the addition of disodium hydrogen orthophosphate and the aqueous solution was extracted repeatedly with ethyl acetate. The organic extracts were dried over magnesium sulfate and evaporated. After recrystallization of the residue from acetone, there were obtained 1.1 g of hexahydro-2-mercaptomethyl-3-oxo-1H- pyrazolo[1,2-a]pyridazine-5-carboxylic acid having a melting point of 145.5°-147° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:13]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][C:26]([CH3:28])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:25][CH:26]([N:22]1[CH2:23][CH2:24][CH:19]([N:14]2[CH:15]=[CH:16][C:17](=[O:18])[C:12]([C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[CH:9][CH:10]=3)=[N:13]2)[CH2:20][CH2:21]1)[CH3:28]
Reactant: CC(C)=O
Reactant: O=c1ccn(C2CCNCC2)nc1-c1ccnn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)N1CCC(n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(1-Phenyl-1H-pyrazol-5-yl)-1-piperidin-4-ylpyridazin-4(1H)-one (0.20 g), acetone (0.23 mL) and acetic acid (1.0 mL) were dissolved in THF (10 mL), sodium triacetoxyborohydride (0.66 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and neutralized with saturated sodium hydrogen carbonate. Sodium chloride was added to saturation, and the mixture was extracted with ethyl acetate/THF. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, THF) and recrystallized from ethyl acetate/hexane to give the title compound (0.15 g).
Reaction SMILES: [Na].[CH2:2]([SH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14][CH:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]=1[CH:27]=[O:28]>CO>[CH2:2]([S:9][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14][CH:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]=1[CH:27]=[O:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SCc1ccccc1
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: [Na]
Solvent: CO
Product: O=CC1=C(SCc2ccccc2)c2ccccc2OC1c1ccccc1
Reaction time: 0.25 h

Procedure:
1.25 g sodium is allowed to react with 150 ml absolute methanol. When all the sodium has disappeared, one adds 6 ml benzylmercaptan and 13.5 g 4-chloro-3-formyl-flav-3-ene and refluxes over 15 minutes. After solvent evaporation and extraction with methylene chloride the residue is crystallized in a mixture of hexane and diisopropylether. Pure 4-benzylmercapto-3-formyl-flav-3-ene is obtained as yellow crystals; m.p. 99°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Reactant: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COc1cc(CC(=O)N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the product of EXAMPLE 30B (1 g, 4.74 mmol) in thionyl dichloride (20 mL) was stirred at reflux for 3 hours. The solution was concentrated and the residue was diluted with dry dichloromethane (20 mL) and dropped into a solution of pyrrolidine (0.63 mL, 7.1 mmol) and diisopropyl ethylamine (1.7 mL, 9.5 mmol). The mixture was stirred at room temperature overnight and the mixture was washed with 1N aqueous hydrochloric acid (20 mL) and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated and the residue was purified by flash chromatography on silica gel eluting with 1/100 methanol/dichloromethane to give the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][NH:8][C:7]=2[C:6](=[O:12])[NH:5][C:4]1=[O:13])[CH3:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:14]([N:8]1[C:7]2[C:6](=[O:12])[NH:5][C:4](=[O:13])[N:3]([CH2:1][CH3:2])[C:11]=2[N:10]=[CH:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CCn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1

Procedure:
18 g (0.1 mol) of 3-ethylxanthine were stirred at 60° C. for 2 hours with 19.2 g (0.11 mol) of benzyl bromide and 15.2 g (0.11 mol) of potassium carbonate. The reaction solution was transferred to an Edenmeyer flask and treated with 1000 ml of water. The precipitate was filtered off with suction, washed several times with warm water and dried at 50° C. under reduced pressure.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.N1(O)C2C=CC=CC=2N=N1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][O:37][C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)=[C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: Oc1cccnc1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1ccc(-c2nc3ccc(C)cn3c2COc2cccnc2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 1H-benzo[d][1,2,3]triazol-1-ol. and pyridin-3-ol. m/e+ 350 for C21H20N3O [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.38 (d, J=1.8 Hz, 1H), 8.27 (dd, J=1.8, 4.4 Hz, 1H), 8.21 (d, J=2.5 Hz, 1H), 8.02 (d, J=4.4 Hz, 1H), 7.91 (s, 1H), 7.59 (dd, J=1.4, 8.0 Hz, 2H), 7.23 (d, J=1.4, 8.0 Hz, 2H), 7.15 (m, 2H), 5.42 (s, 2H), 2.36 (s, 3H), 2.35 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[CH2:13]([O:15][CH:16]([O:22]CC)[C:17](OCC)=O)C>C[N+]([O-])=O>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:17]([C:16]([O:15][CH3:13])=[O:22])[O:10][CH2:9][CH2:8]2
Reactant: COc1c(Br)cccc1CCO
Reactant: CCOC(=O)C(OCC)OCC
Solvent: C[N+](=O)[O-]
Product: COC(=O)C1OCCc2c1ccc(Br)c2OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-(3-bromo-2-methoxyphenypethanol To a solution of methyl (3-bromo-2-methoxyphenyl)acetate (8.2 g, 31.66 mmol) in 200 mL of dry THF under N2 at room temperature was added LiBH4 (32 mL, 63.32 mmol, 2M THF). After 1.5 hours, the reaction was warmed to reflux for 3 hours, and then cooled to room temperature. The solution was poured into EtOAc/1N HCl solution, and the layers were separated. The organic layer was washed with water, saturated Na2CO3 and brine, dried over anhydrous Na2SO4 and concentrated to give 2-(3-bromo-2-methoxyphenyl)ethanol. Step E: methyl 6-bromo-5-methoxy-3,4-dihydro-1H-isochromene-1-carboxylate TiCl4 (9.84 g, 104 mmol) was added over a period of 20 min to an ice-cooled mixture of 2-(3-bromo-2-methoxyphenyl)ethanol (6 g, 26.0 mmol) and ethyl diethoxyacetate (5.5 g, 31.1 mmol) in 60 mL of CH3NO2. After stirred for 10 min, the ice bath was removed and the mixture was allowed to stir at room temperature over night. The mixture was poured onto ice/aqueous 1N HCl. Extracted by DCM and backwashed with 1N HCl and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified via column chromatograph to give methyl 6-bromo-5-methoxy-3,4-dihydro-1H-isochromene-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: COc1ccc(N)cn1
Product: COc1cccc(CC(=O)Nc2ccc(OC)nc2)c1
Yield: 98.9 %

Procedure:
The title compound was prepared as described in Example 1.A, using 3-methoxyphenylacetyl chloride (4.8 g, 26.0 mmol) and 5-amino-2-methoxypyridine (3.23 g, 26.0 mmol) to afford the title compound (7.0 g, 99% yield): ES-MS (m/z) 272.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[C:13]#[N:14])([O-])=O.[CH2:15]([N:17]1[CH2:22][CH2:21]N[CH2:19][CH2:18]1)[CH3:16].O>CN(C=O)C>[CH2:15]([N:17]1[CH2:22][CH2:21][N:1]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=2[C:13]#[N:14])[CH2:19][CH2:18]1)[CH3:16]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCN1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCN(c2cccc([N+](=O)[O-])c2C#N)CC1
Temperature: 90 °C

Procedure:
2,6-Dinitrobenzenecarbonitrile (1.0 eq) and ethylpiperazine (3.6 eq) were dissolved in DMF. The resulting solution heated at 90° C. for 2 hours. The solution was cooled to room temperature and poured into H2O. A precipitate formed which was filtered to yield the desired product as a brown solid. LC/MS m/z 260.1 (MH+), Rt 1.69 minutes.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C@H:8]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=3)[CH2:9][N:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:11][C@@H:6]2[CH:5]=[CH:4][CH2:3]1.[H][H]>CO.[Pt]=O>[O:1]=[C:2]1[N:7]2[C@H:8]([C:16]3[CH:17]=[C:18]([F:24])[C:19]([F:23])=[C:20]([F:22])[CH:21]=3)[CH2:9][N:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:11][C@@H:6]2[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)N1C[C@@H]2C=CCC(=O)N2[C@H](c2cc(F)c(F)c(F)c2)C1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: COC(=O)N1C[C@@H]2CCCC(=O)N2[C@H](c2cc(F)c(F)c(F)c2)C1

Procedure:
Platinum oxide (10 mg) was added to a solution of methyl (4R*,9aS*)-6-oxo-4-(3,4,5-trifluorophenyl)-1,3,4,6,7,9a-hexahydropyrido[1,2-a]pyrazine-2-carboxylate obtained by performing the above method again (292 mg) in methanol (5 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for three hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 255 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2C)[CH2:6][CH2:5]1)=[O:3].[F:17]C1C=CC=CC=1N1CCNCC1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>ClCCl>[Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[CH2:6][CH2:5]1)=[O:3]
Reactant: Cc1ccccc1N1CCN(C(=O)Cl)CC1
Reactant: Fc1ccccc1N1CCNCC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)N1CCN(c2ccccc2F)CC1
Yield: 88 %

Procedure:
Compound 41A is prepared according to the procedure described for compound 15A, using the following reactants: 1-(2-fluorophenyl)piperazine (1.54 g, 8.06 mmol); triphosgene (850 mg, 2.85 mmol); pyridine (0.69 ml, 8.6 mmol); dichloromethane (60 ml).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.Cl.[F:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:25][C:26](O)=[O:27].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH:7][C:26](=[O:27])[CH2:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[N:17]=[CH:16][C:15]([F:14])=[CH:24]3)[S:5][CH:6]=1
Reactant: O=C(O)Cc1cccc2cc(F)cnc12
Reactant: Nc1scc(Br)c1-c1nnc[nH]1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1cccc2cc(F)cnc12)Nc1scc(Br)c1-c1nc[nH]n1
Reaction time: 1 h

Procedure:
4-Bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (17 mg, 69.4 umol), 2-(3-fluoroquinolin-8-yl)acetic acid hydrogen chloride (22 mg, 91.0 umol), 2-chloro-1-methylpyridinium iodide (101 mg, 395 umol) and triethylamine (0.2 ml) in methylene chloride (1 ml) was heated to reflux. After stirring for 1 h, the solution was concentrated and the residue was purified by HPLC to yield N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3-fluoroquinolin-8-yl)acetamide. Method [7] retention time 5.67 min by HPLC (M+432 and 434) and (M+Na 454 and 456). 1H NMR (300 MHz, CDCl3) δ 12.25 (s, 1H), 8.83 (d, J=3.3 Hz, 1H), 7.87 (m, 2H), 7.80 (d, J=6.0 Hz, 1H), 7.73 (s, 1H), 7.66 (t, J=7.8 Hz, 1H), 6.90 (s, 1H), 6.70 (broad s, 2H), 4.56 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][CH2:18][CH2:19][OH:20])=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:20][CH2:19][CH2:18][CH2:17][C:16]1[C:12]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)=[O:11])=[N:13][O:14][N:15]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCO
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Temperature: 0 °C
Yield: 79.4 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-4-(3-hydroxypropyl)-1,2,5-oxadiazole-3-carboxamide (60 mg, 0.20 mmol) was dissolved in anhydrous DCM (2 mL), followed by addition of TEA (57 μL, 0.41 mmol). The reaction was stirred and cooled to 0° C., and methanesulfonyl chloride (29 μL, 0.37 mmol) was added drop-wise. The reaction was quenched with water and diluted with DCM. The organic layer was separated, dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography (25%-75% EtOAc/hexane) to give the desired product (60 mg, 80%). LCMS for C13H14ClFN3O5S (M+H)+: m/z=378.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:29][CH:28]=1)(C(C)(C)C)(C)C>C1COCC1>[OH:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCCCNC(=O)OCc2ccccc2)c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NCCCCc1ccc(O)c2ccccc12)OCc1ccccc1
Reaction time: 2 h
Yield: 102.7 %

Procedure:
Tetrabutylammonium fluoride (1 M in THF, 1.0 mL) was added to a solution of benzyl 4-[4-(tert-butyldimethylsilyloxy)naphthalen-1-yl]butylcarbamate (19, 380 mg, 0.80 mmol) in anhydrous THF (15 ml) at room temperature. The reaction mixture was stirred for 2 h and concentrated to dryness. The residue was purified by column chromatography (silica gel, 3:1 hexanes/EtOAc) to afford butylcarbamate 20 (287 mg, 99%) as white solid: 1H NMR (300 MHz, CDCl3) δ 8.23-8.21 (m, 1H), 7.84-7.81 (m, 1H), 7.42-7.34 (m, 2H), 7.25-7.15 (m, 5H), 6.96 (d, J=7.5 Hz, 1H), 6.62 (d, J=7.5 Hz, 1H), 5.00 (br s, 2H), 4.65 (br s, 1H), 3.13 (q, J=6.6 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 1.64-1.47 (m, 4H).
Reaction SMILES: [Br:1]Br.[CH3:3][S:4]([N:7]1[CH2:12][CH2:11][CH2:10][S:9][C:8]1=[CH:13][N+:14]([O-:16])=[O:15])(=[O:6])=[O:5].CCOCC>C(Cl)Cl>[CH3:3][S:4]([N:7]1[CH2:12][CH2:11][CH2:10][S:9][C:8]1=[C:13]([Br:1])[N+:14]([O-:16])=[O:15])(=[O:5])=[O:6]
Reactant: BrBr
Reactant: CS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)N1CCCSC1=C(Br)[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A solution of 1.6 g of bromine in 10 ml of methylene chloride was added drop-by-drop over a period of 10 minutes to a solution of 2.38 g of (1A) in 50 ml of methylene chloride at 0° C. and under a nitrogen blanket. The resulting mixture was stirred for a further 10 minutes, charcoaled, and stripped of solvent. The residue was dissolved in a minimum amount of methylene chloride, then ether was added to the solution, resulting in a gum. The gum was dissolved in methylene chloride, the solution was charged onto a flash chromatograph column (silica gel) and the product was eluted with methylene chloride, to give (1) on workup.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[O:7][C:6](=[O:8])[CH:5]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[C:4](=[O:25])[O:3]1.C([Si](C)(C)N1C2=NC=CC([Cl:41])=C2C=C1)(C)(C)C>>[Cl:41][C:17]1[CH:16]=[CH:15][N:14]=[C:13]2[NH:12][CH:11]=[C:10]([CH:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:5]3[C:6](=[O:8])[O:7][C:2]([CH3:26])([CH3:1])[O:3][C:4]3=[O:25])[C:18]=12
Reactant: CC1(C)OC(=O)C(C(c2ccccc2)c2c[nH]c3ncccc23)C(=O)O1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2c(Cl)ccnc21
Product: CC1(C)OC(=O)C(C(c2ccccc2)c2c[nH]c3nccc(Cl)c23)C(=O)O1

Procedure:
5-[(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione was prepared following the procedure described for preparation of 2,2-dimethyl-5-[phenyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-[1,3]dioxane-4,6-dione in example 1, using 1-(tert-butyl-dimethyl-silanyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.[C:12](ON1C(=O)CCC1=O)([O:14][CH2:15][CH:16]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13]>C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>[N:6]1([C:12]([O:14][CH2:15][CH:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]3[C:28]2=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:13])[CH2:7][CH:8]([OH:10])[CH2:9][C@H:5]1[C:4]([O:3][CH3:2])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CC(O)CN1C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
L-hydroxyproline methylester hydrochloride is reacted with Fmoc-OSu in aqueous 1.0 N sodium carbonate/THF at room temperature. After completion of the reaction, Fmoc-Pro(4-OH)—OMe is isolated by precipitation. Fmoc-Pro(4-OH)—OMe is then added dropwise into a solution of trisphosgene (0.6 eq.) in THF to give a chlorocarbonate intermediate. After 1 h dimethylaminopyridine (1.0 eq.) and N-Boc-diaminoethane (6.0 eq.) are added and the reaction is stirred at room temperature. After completion of the reaction, the solvent is removed in vacuo and the resulting Fmoc-Pro(4-OCO—NH—CH2—CH2—NH-Boc)-OMe is extracted from a two phase system of ethyl acetate/0.1 M HCl to give crude product (MH+=554) which is purified by crystallization from ethyl acetate. The methyl ester is then cleaved to the free acid by treatment with 1N NaOH in dioxane/water and the product Fmoc-Pro(4-OCO—NH—CH2—CH2—NH-Boc)-OH is purified on silica gel, [(M+Na)]+=562).