Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][C:5](Cl)=O)[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[C:13]([S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:21][CH2:22][CH:23]1[CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:21]2[C:10]3[CH:11]=[CH:12][C:13]([S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[CH:14][C:9]=3[N:8]=[C:5]2[CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH2:24][CH2:25]1
Reactant: O=C(Cl)CC1CC1
Reactant: CC(C)S(=O)(=O)c1ccc(NCC2CC2)c(N)c1
Product: CC(C)S(=O)(=O)c1ccc2c(c1)nc(CC1CC1)n2CC1CC1

Procedure:
The title compound was prepared according to the procedure described in Step C of Example 5 from cyclopropylacetyl chloride (Step A) and 2-amino-1-(N-cyclopropylmethylamino)-4-(isopropylsulfonyl)benzene (Step E of Example 1).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19]3[NH:23][N:22]=[N:21][N:20]=3)=[CH:13][CH:12]=2)[C:8]([S:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[OH:41]O>C(O)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19]3[NH:20][N:21]=[N:22][N:23]=3)=[CH:15][CH:16]=2)[C:8]([S:30]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=2)=[O:41])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OO
Reactant: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(c2ccccc2)c2nnn[nH]2)cc1
Solvent: CC(=O)O
Product: CCCCc1nnc(S(=O)Cc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(c2ccccc2)c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
To a stirred solution of 3-Butyl-4-[[4-[1-phenyl-1-(tetrazol-5-yl)methoxy]phenyl]methyl]-5-(4-nitrobenzylthio)-4H-1,2,4-triazole (from Example 3, Step C) in glacial acetic acid is added gradually an equal volume of 30% hydrogen peroxide (aqueous). The resulting solution is stirred at room temperature in a stoppered flask for about 15-20 hours, until TLC and/or NMR (from work-up of an aliquot) indicates complete reaction. The reaction mixture is then partitioned between ethyl acetate and dilute HCl. The ethyl acetate phase is dried (MgSO4), filtered, and concentrated in vacuo. The residue is triturated with ether to give the title compound as a solid, which is collected on a filter and washed further with ether.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:16]=[C:15]2[C:6]([S:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:17]([N:19]=[C:20]=[S:21])=[O:18])[C:13]=3[NH:14]2)=[CH:5][CH:4]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[S:7][C:8]3[C:13]4=[C:12]([C:17](=[O:18])[NH:19][C:20](=[S:21])[N:14]4[C:15]=2[CH:16]=1)[CH:11]=[CH:10][CH:9]=3
Reactant: O=C(N=C=S)c1cccc2c1Nc1cc(C(F)(F)F)ccc1S2
Solvent: Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1[nH]c(=S)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2

Procedure:
A slurry of 53.7 g. (0.168 mol.) of 8-trifluoromethylphenothiazine-1-carboxylic acid isothiocyanate in 30 ml. of diphenyl ether was heated in an oil bath at 210° for one hour. The reaction mixture first became a homogenous liquid and then turned into a solid mass. The cooled reaction mixture was refluxed for several minutes in 100 ml. of toluene, cooled to ambient temperature, and the insoluble material was collected by filtration and washed with several small portions of toluene to give the title compound, m.p. 297°-299° (ethanol).
Reaction SMILES: [Br-].Br[S+:3]([CH3:5])[CH3:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:4][S:3][CH2:5][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH2:6]
Reactant: C[S+](C)Br
Agent: [Br-]
Solvent: Nc1ccccc1
Product: CSCc1ccccc1N
Yield: 69 %

Procedure:
Through this general procedure p-anisidine could be converted into 4-methoxy-2-(methylthiomethyl)aniline in 62 percent yield. The procedure is quite general. For a series of anilines (toluidine, aniline, p-chloroaniline, 4-nitroaniline, and p-ethoxycarbonylaniline) reaction of the aniline with the chlorine:sulfur compound complex chlorodimethylsulfonium chloride through the azasulfonium halide salt gave the corresponding 2-(methylthiomethyl)anilines in 54, 67, 45, 31 and 35% yields, respectively. The reaction is not restricted to chlorodialkylsulfonium chlorides. For example, when bromodimethylsulfonium bromide was used with aniline to form the azasulfonium bromide salt of aniline a 69 percent yield of 2-(methylthiomethyl)aniline was obtained. Treatment of aniline with halotetramethylenesulfonium halide (chloride or bromide) to form the azasulfonium salt followed by base treatment, gave 2-(2-tetrahydrothienyl)aniline in 20 percent yield. The use of β-keto sulfides and β-carboalkoxysulfides in the reaction provided a simple route to indoles and 2-oxindoles. Treatment of p-anisidine with chlorine:sulfur compound complex ##EQU8## to form the azasulfonium halide salt of the anisidine, followed by triethylamine, according to the above general procedure, gave 2-methyl-5-methoxy-3-methylthioindole in 38 percent yield. The reaction is not restricted to p-anisidine. With aniline, p-chloroaniline, and benzocaine, we obtained the corresponding unsubstituted, 5-chloro- and 5-ethoxycarbonyl-2-methyl-3-methylthioindoles in 68, 45 and 33 percent yields, respectively. Raney nickel desulfurization of the 3-methylthio compound gave 5-methoxy-2-methylindole in 72 percent yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CCO>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][NH:13][C:12]=2[N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc2cccnc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCc1ccc2c(n1)NCCC2

Procedure:
A mixture of 10-5 (5.0 g, 20.4 mmol), 10% Pd/C (2.5 g), and EtOH (200 mL) was stirred under a balloon of hydrogen for 15 h. The mixture was filtered, and the filtrate concentrated to give 10-6 as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C@H:9]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7][CH:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[C:21]1([CH2:20][O:19][C@@H:8]2[C@@H:9]([CH2:10][O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:5]([CH2:3][OH:2])=[CH:6][CH2:7]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C1=CC[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCC1=CC[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a round bottomed flask equipped with an argon inlet, magnetic stirrer and cooling bath was dissolved (4S, 5R)-4-(Phenylmethoxy)-5-[(phenylmethoxy)methyl]-1-cyclopentene-1-carboxylic acid methyl ester 7 (3.62 g, 10.2 mmol) in DCM (40 mL). The solution was cooled to −78° C. and diisobutylaluminum hydride (1 M in toluene, 22.4 mL, 22.4 mmol) was added into the solution over the course of 10 minutes. After stirring at −78° C. for 1 hour the reaction mixture was quenched with a saturated solution of potassium sodium tartrate (Rochelle salt, 50 mL) and stirred at room temperature overnight. The organic layer was diluted with ethyl acetate, separated, dried (sodium sulfate) and concentrated in vacuo to afford the crude allylic alcohol as colorless oil (3.06 g, 90%). After standing at room temperature the title compound crystallized out as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([O:9][CH2:10][CH3:11])=[CH:7][C:6]([O:12][CH2:13][CH3:14])=[CH:5][N:4]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)[N:17]=1>CN(C=O)C.O>[F:15][C:16]1[N:17]=[C:18]([C:22]2[N:26]([CH2:2][C:3]3[C:8]([O:9][CH2:10][CH3:11])=[CH:7][C:6]([O:12][CH2:13][CH3:14])=[CH:5][N:4]=3)[CH:25]=[CH:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Reactant: CCOc1cnc(CCl)c(OCC)c1
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cnc(Cn2ccnc2-c2cccc(F)n2)c(OCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 2-chloromethyl-3,5-diethoxy-pyridine (174 mg, 0.69 mmol) in DMF (5 mL) is added 2-fluoro-6-(1H-imidazol-2-yl)-pyridine (112 mg, 0.69 mmol), and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The residue is purified by column chromatography eluting with 8% MeOH—CH2Cl2 containing few drops of NH4OH to afford 2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-yl methyl]-3,5-diethoxy-pyridine (118 mg, 49%); 1H NMR (300 MHz, CDCl3): 8.06 (dd, J=5.1, 2.4 Hz, 1H), 7.81 (t, J=7.9 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.09 (s, 1H), 7.04 (s, 1H), 6.80 (dd, J=5.1, 2.7 Hz, 1H), 6.65 (d, J=2.4 Hz, 1H), 5.95 (s, 2H), 4.02 (q, J=6.9 Hz, 2H), 3.90 (q, J=6.9 Hz, 2H), 1.39 (t, J=6.9 Hz, 2H), 1.16 (t, J=6.9 Hz, 2H), m/z 343 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH3:35][N:36]([CH3:44])[C:37]([N:39]([CH3:43])[CH2:40][C:41]#[CH:42])=[O:38].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:42]#[C:41][CH2:40][N:39]([CH3:43])[C:37]([N:36]([CH3:44])[CH3:35])=[O:38])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: C#CCN(C)C(=O)N(C)C
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCN(C)C(=O)N(C)C)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Reaction time: 3 h
Yield: 68.6 %

Procedure:
This was prepared using the method described in example 26 but it was carried out at room temperature over 3 hr using N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4ylpropoxy)quinazolin-4-amine (310 mg, 0.52 mmol), N,N,N′-trimethyl-N′-prop-2-yn-1-ylurea (145 mg, 1.04 mmol), bis(triphenylphosphine) palladium(II) dichloride (36 mg, 10 mol %), copper(I) iodide (10 mg, 10 mol %) and diisopropylamine (105 mg, 1.04 mmol) in ethyl acetate (10 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent to give the title compound (218 mg, 69%) as a pale brown solid; NMR Spectrum:(CDCl3) 2;11 (quintet, 2H), 2.48 (m, 4H), 2.56 (t, 2H), 2.87 (s, 6H), 2.92 (s, 3H), 3.72 (m, 4H), 4.00 (s, 3H), 4.15 (s, 2H), 4.25 (t, 2H), 6.06 (s, 2H), 7.03 (s, 1H), 7.10-7.30 (s(broad), 1H), 7.20 (s, 1H), 7.31 (s, 1H), 8.60 (s, 1H); Mass Spectrum: M+H+ 611/613.
Reaction SMILES: [N+](C1C=CC=CC=1O[C:11](=[O:35])[C@@H:12]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.[CH:36]1[CH:41]=[CH:40][C:39]([C@@H:42]([NH2:45])[CH2:43][OH:44])=[CH:38][CH:37]=1>C(Cl)Cl>[C:14]([NH:13][C@@H:12]([C:11]([NH:45][C@H:42]([C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1)[CH2:43][OH:44])=[O:35])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Yield: 69.8 %

Procedure:
Prepared according to the method described in Example 4(b) above from Nα -Boc-Nδ -Cbz-(R)-ornithine o-nitrophenyl ester (5.0 g; 11.5 mmol; see Example 4(a) above), (R)-(-)-phenylglycinol (1.58 g; 11.5 mmol) and 160 mL of CH2Cl2, yielding 3.9 g of the sub-title compound as a white solid.
Reaction SMILES: [CH3:1][Li].[ClH:3].[C:4]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH:14]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]2)([OH:6])=O.O>CCOCC>[ClH:3].[C:4]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH:14]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]2)(=[O:6])[CH3:1]
Reactant: [Li]C
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)O)c2C1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(C(C)=O)c2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56 %

Procedure:
A 5% solution of methyl lithium in ether (0.6 ml, 0.96 mmol) was added to a chilled slurry of (±)-8-Carboxy-2-(dipropylamino)tetralin hydrochloride (100 mg, 0, 32 mmol) in ether. The mixture was stirred at room temperature and under nitrogen for three days. Water was added carefully and the mixture was extracted with ether. The organic layer was dried (potassium carbonate) and concentrated. The residue was purified by chromatography on an alumina column eluted with ether/light petroleum 1:4. The pure fractions were pooled, concentrated and converted into the hydrochloride. Recrystallization from acetonitrile/ether gave 55 mg (56%) of pure 8-acetyl-2-(dipropylamino)tetralin hydrochloride.
Reaction SMILES: [H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH2:26]([CH2:33][C:34](=[O:36])[CH3:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([N:5]3[CH:4]([CH2:35][C:34](=[O:36])[CH2:33][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:13])=[N:15]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CC(=O)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCc3ccccc3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
An oily suspension (50% by weight; 4.7 g) of sodium hydride is added at a temperature in the region of 0° C. to a solution, maintained under a nitrogen atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (15 g) in anhydrous dimethylformamide (280 cc), and the suspension obtained is stirred for 30 minutes at a temperature in the region of 0° C. A solution of benzylacetone (14.4 g) in anhydrous dimethylformamide (20 cc) is added and stirring is continued for 21 hours at a temperature in the region of 0° C. The reaction mixture is then poured into distilled water (1.5 litres). The pH of the aqueous phase is brought to approximately 5 by adding 4 N aqueous hydrochloric acid solution. The product i$ extracted with methylene chloride (3×500 cc). The organic phases are combined and washed with distilled water (3×80 cc), dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). The oily residue obtained is purified by chromatography under pressure (50 kPa) on silica gel (0.040-0.063 mm; 200 g) contained in a column 2.8 cm in diameter. Elution is performed with methylene chloride, collecting 50-cc fractions. Fractions 9 to 21 are combined and concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). After the solid obtained is recrystallized in ethanol, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(2-oxo-4-phenylbutyl)-1-isoindolinone (3.4 g), m.p. 180° C., is obtained.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:38])([CH3:37])[C@@H:14]([O:29]CC1C=CC=CC=1)[C:15]([O:17][CH2:18][O:19][C:20](=[O:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:38])([CH3:37])[C@@H:14]([OH:29])[C:15]([O:17][CH2:18][O:19][C:20](=[O:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)OCOC(=O)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCOC(=O)Cc1ccccc1
Reaction time: 8 h
Yield: 19.8 %

Procedure:
Following the general procedure of hydrogenolysis of benzyl ethers of Description 18, a mixture of (2-phenylacetyloxy)methyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (28c) (60 mg, 0.11 mmol) and 60 mg of 10 wt.-% of palladium on activated carbon in 2 mL of ethanol (EtOH) was stirred overnight under a hydrogen atmosphere. After purification by mass-guided preparative HPLC, 10 mg (20% yield) of the title compound (28) was obtained as a colorless, viscous oil. 1H NMR (400 MHz, CDCl3): δ=0.91 (s, 3H), 1.00 (s, 3H), 1.98 (s, 3H), 2.03-2.10 (m, 2H), 3.10-3.23 (m, 2H), 3.26 (br., 1H), 3.32-3.45 (m, 2H), 3.70 (s, 2H), 3.90 (d, J=9.6 Hz, 1H), 4.07 (s, 1H), 4.10 (d, J=9.2 Hz, 1H), 5.79 (d, J=5.6 Hz, 1H), 5.85 (br. m, 1H), 5.93 (d, J=5.6 Hz, 1H) 7.26-7.35 (m, 5H) ppm. MS (ESI) m/z: 460.05 (M+H)+, 481.99 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: CN(C=O)C.P(Cl)(Cl)([Cl:8])=O.[Br:11][C:12]1[CH:21]=[CH:20][C:15]2[NH:16][C:17](=O)[S:18][C:14]=2[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>O>[Br:11][C:12]1[CH:21]=[CH:20][C:15]2[N:16]=[C:17]([Cl:8])[S:18][C:14]=2[CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nc2ccc(Br)cc2s1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
DMF (0.807 mL, 10.4 mmol) was added to phosphorous oxychloride (8.10 mL, 86.9 mmol), and the reaction mixture was stirred for 15 min. 6-bromobenzo[d]thiazol-2(3H)-one (2.00 g, 8.69 mmol) was added and the reaction mixture was heated to 100° C. overnight. Upon cooling to rt, the reaction mixture was slowly added to a solution of K2CO3 (75 g) in water (200 mL) while maintaining the temperature below 35° C. Additional K2CO3 was added in order to maintain the pH above 10. Upon complete addition, the mixture was allowed to stir for 1 h. The solid was collected by filtration, washed with water (2×25 mL), and air dried. Further drying in a vacuum oven gave 2.06 g (95%) of the desired product as a brown solid. The material was used without further purification. LC-MS: RT=9.94 min., compound does not ionize.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][CH2:10][CH2:11]Br>>[Br:9][CH2:10][CH2:11][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Oc1ccccc1Cl
Reactant: BrCCBr
Product: Clc1ccccc1OCCBr

Procedure:
2-Chlorophenol was reacted with 1,2-dibromoethane according to the procedure described in Step 2A to yield the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:33])(=[N:29][CH2:30][CH2:31]Br)=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:33])(=[N:29][CH2:30][CH2:31][N:36]([CH2:37][CH3:38])[CH2:34][CH3:35])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CS(=O)(=NCCBr)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: CCNCC
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCN=S(C)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 2 h
Yield: 60 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl-N-[2-bromo-ethyl]sulfoximide (150 mg, 0.00026 mol) in DMF(0.7 mL) was added diethyl amine (1 mL) at 25° C. Reaction mixture was stirred at same temperature for 2 hr. Reaction mixture was diluted with water and filtered. Drying afforded 85 mg of titled compound in 60% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:34]3[C:10](=[C:11]4[C:31](=[CH:32][CH:33]=3)[C:15]3[N:16]=[C:17]([C@@H:19]5[CH2:23][CH2:22][CH2:21][N:20]5[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:18][C:14]=3[CH2:13][CH2:12]4)[O:9][CH2:8][C:6]=2[CH:7]=1>ClCCl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:34]3[C:10](=[C:11]4[C:31](=[CH:32][CH:33]=3)[C:15]3[N:16]=[C:17]([C@@H:19]5[CH2:23][CH2:22][CH2:21][N:20]5[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:18][C:14]=3[CH:13]=[CH:12]4)[O:9][CH2:8][C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c([nH]1)CCc1c-2ccc2c1OCc1cc(Cl)ccc1-2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c(ccc3c4c(ccc32)-c2ccc(Cl)cc2CO4)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
To a solution of Intermediate tert-butyl(2S)-2-(9-chloro-3,4,5,7-tetrahydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.43 g, 3.0 mmol) in dichloromethane (30 mL) was added manganese(IV) oxide (15 g, 198 mmol). The mixture was stirred for four hours at room temperature then filtered through Celite. The MnO2 was thoroughly rinsed with dichloromethane and the total filtrate was concentrated to yield tert-butyl(2S)-2-(9-chloro-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.37 g, 96% yield). This material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([O:11]C)[C:5]2=[N:4][CH:3]=1.C(=O)([O-])O.[Na+]>Br.O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][NH:9][C:10](=[O:11])[C:5]2=[N:4][CH:3]=1
Reactant: COc1nccn2c(Br)cnc12
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=c1[nH]ccn2c(Br)cnc12
Temperature: 80 °C

Procedure:
A suspension of 3-bromo-8-methoxyimidazo[1,2-a]pyrazine (1.6 g, 7 mmol) in hydrogen bromide (30 wt % in acetic acid, 15 ml) was heated at 80° C. for 90 min. The reaction was cooled, diluted with water (75 ml) then neutralised with solid sodium hydrogencarbonate. The resulting solid was collected by filtration, washed with water then dried under vacuum to afford 3-bromo-7H-imidazo[1,2-a]pyrazin-8-one as a white powder: δH (360 MHz, DMSO) 6.99 (1H, d, J 5.6), 7.29 (1H, d, J 5.6), 7.62 (1H, s). This powder was suspended in N,N-dimethylformamide (15 ml) then treated with sodium hydride (203 mg of a 60% dispersion in mineral oil, 8.4 mmol). The resulting mixture was heated at 60° C. for 20 min then treated with iodomethane (870 μl, 14 mmol). After stirring for 15 min the reaction was cooled, diluted cautiously with water (150 ml) and then extracted with dichloromethane (2×100 ml). The organics were combined, washed with water, dried over anhydrous magnesium sulphate, filtered and concentrated under high vacuum. The residue was triturated with diethyl ether and the resulting solid collected by filtration to furnish 3-bromo-7-methyl-7H-imidazo[1,2-a]pyrazin-8-one as a white solid (1.4 g, 88% over 2 steps): δH (360 MHz, DMSO) 3.45 (3H, s), 7.28 (1H, d, J 6), 7.39 (1H, d, J 5.6), 7.62 (1H, s).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>>[CH2:12]([NH:15][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH:13]=[CH2:14]
Reactant: C=CCN
Reactant: COC(=O)c1cccnc1Cl
Product: C=CCNc1ncccc1C(=O)OC
Temperature: 140 °C
Yield: 73.6 %

Procedure:
Methyl 2-chloropyridine-3-carboxylate (5 g) was reacted neat with allylamine (3.1 g) with heating at 140° C. for 4 hours. The volatiles were removed under reduced pressure and the residue chromatographed on silica gel eluting with ethyl acetate in hexane to afford 4.12 g of the title compound. MS (DCl/NH3) m/e 207 (M+H)+.