Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][S:22][C:21](=[S:24])[CH:20]=2)=[CH:15][CH:14]=1>CC(C)=O>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][S:22][C:21](=[S:24]=[O:9])[CH:20]=2)=[CH:15][CH:14]=1
Reactant: Oc1ccc(-c2cc(=S)ss2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: O=S=c1cc(-c2ccc(O)cc2)ss1

Procedure:
A solution of 9.4 g 80-90% pure 3-chloroperbenzoic acid (=approximately 0.046 Mol) in 200 ml acetone was added dropwise with vigorous stirring to a solution of 10 g (=0.004 Mol) 5-(4-hydroxyphenyl)-1,2-dithiol-3-thione in 300 ml acetone within one hour at room temperature. Thereafter, the reaction mixture was kept at the same temperature for a further hour. The 5-(4-hydroxyphenyl)-1,2-dithiol-3-thion-S-oxide which resulted as a red precipitate was filtered-off under suction and dried over phosphorus pentoxide. 9.4 g of the S-oxide with a melting point of 118-124° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])([CH3:9])[CH2:5][C:6](=[O:8])[CH:7]=1.[CH2:12]([OH:16])[CH:13](O)[CH3:14].C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:14][CH:13]1[CH2:12][O:16][C:6]2([CH2:5][C:4]([CH3:10])([CH3:9])[C:3](=[O:11])[C:2]([CH3:1])=[CH:7]2)[O:8]1
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Reactant: CC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1=CC2(CC(C)(C)C1=O)OCC(C)O2
Yield: 70.2 %

Procedure:
To a 2 liter flask fitted with a reflux condenser, a water separator and a stirrer is charged 265 g of 2,6,6-trimethylcyclohex-2-en-1,4-dione (prepared by the method described in Helv.Chim.Acta. 39, 2041(1956)), 266 g of propylene glycol, 500 ml of benzene and 1 g of p-toluenesulfonic acid. The reactants are stirred and refluxed until no additional water is collected in the water separator. The product is washed with water to a pH of 6 and the solvent is stripped off. The residue is vacuum distilled through a nine inch Goodloe column to yield 257 g of product, b.p. 92° at 1 mm Hg (80% yield).
Reaction SMILES: Cl.CN.CC(C)(C)C[CH2:7][NH2:8].[O:11]=[C:12]1[C:20]2([C:24]3=[CH:25][C:26]4[O:30][CH2:29][O:28][C:27]=4[CH:31]=[C:23]3[O:22][CH2:21]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[CH2:32][C:33]1[O:37][C:36]([C:38]([F:41])([F:40])[F:39])=[C:35]([C:42]([OH:44])=O)[CH:34]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC(O)=O>>[CH3:7][NH:8][C:42]([C:35]1[CH:34]=[C:33]([CH2:32][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3([C:24]4=[CH:25][C:26]5[O:30][CH2:29][O:28][C:27]=5[CH:31]=[C:23]4[O:22][CH2:21]3)[C:12]2=[O:11])[O:37][C:36]=1[C:38]([F:40])([F:41])[F:39])=[O:44]
Reactant: O=C(O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F
Reactant: CC(C)(C)CCN
Agent: CN
Agent: Cl
Agent: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Product: CNC(=O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F

Procedure:
Following the procedure as described in EXAMPLE 12.49 and making non-critical variations using methylamine hydrochloride to replace 3,3-dimethylbutylamine, 5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylic acid to replace (2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)acetic acid, N-methyl-5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxamide was obtained (96%) as a colorless solid: mp 202-203° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ7.31-7.27 (m, 2H), 7.19-7.17 (m, 1H), 7.10-7.05 (m, 1H), 6.95-6.92 (m, 1H), 6.62 (s, 1H), 6.49 (s, 1H), 6.09 (s, 1H), 5.94 (br s, 1H), 5.85-5.84 (m, 2H), 5.03-4.85 (m, 3H), 4.67-4.64 (m, 1H), 2.92 (d, J=3.0 Hz, 3H); MS (ES+) m/z 487.3 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.[C:14]([O:23][CH3:24])(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:17].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[C:14]([O:23][CH3:24])=[O:22])=[O:13])=[CH:2]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1NC(=O)Cc1c[nH]c2ccccc12
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
[Route A/E modified] To a solution of 3-indoleacetic acid (5.79 g, 33.1 mmol) in 100 ml THF at room temperature was added 1,1-carbonyldiimidazole (5.36 g, 33.1 mmol). The reaction mixture was stirred for 15 minutes under nitrogen. Methyl anthranilate (5.0 g, 33.1 mmol) and PPTS (20.0 g, 80 mmol) were added to the reaction mixture which was then stirred at reflux for 24 hours, cooled, and concentrated to near dryness in vacuo. The product residue was partitioned between 1N hydrochloric acid and ethyl acetate. The two-phase mixture was heated until two clear layers were obtained. The aqueous layer was separated and the organic layer was allowed to cool, washed (water, lN NaOH, and brine), dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness. The resulting product was triturated with ethyl acetate/hexane and collected by vacuum-assisted filtration to give 8.85 g of 2-(3-indolyl)-N-(2-methoxycarbonylphenyl)acetamide as a pale yellow granular solid which was deesterified by refluxing it in a mixture of 100 ml of methanol and 32 ml of lM NaOH for 30 minutes. The product acid was isolated by concentrating the deesterification mixture in vacuo, acidifying with 40 ml of lN hydrochloric acid, and then extracting it into ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness. Trituration with ethyl acetate/hexanes and vacuum-assisted filtration provided 8.0 g of 2-(3-indolyl)-N-(2-carboxyphenyl)acetamide as an off-white solid: mp 205°-207° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:47])[O:13][CH2:14][C@@H:15]([N:33]([CH3:46])[C:34]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=2F)=[O:35])[CH2:16][C@@H:17]([OH:32])[CH2:18][O:19][P:20]([O:27]C(C)(C)C)([O:22]C(C)(C)C)=[O:21])[N:2]=1.[ClH:48]>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:47])[O:13][CH2:14][C@@H:15]([N:33]([CH3:46])[C:34]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=2[Cl:48])=[O:35])[CH2:16][C@@H:17]([OH:32])[CH2:18][O:19][P:20]([OH:27])([OH:22])=[O:21])[N:2]=1
Reactant: CN(C(=O)NCc1cccc(F)c1F)[C@H](COC(=O)Nc1cc2ccccc2cn1)C[C@@H](O)COP(=O)(OC(C)(C)C)OC(C)(C)C
Reactant: Cl
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)C[C@@H](O)COP(=O)(O)O
Reaction time: 0.5 h

Procedure:
To a solution of the crude (2S,4R)-5-(di-tert-butoxyphosphoryloxy)-2-(3-(2,3-difluorobenzyl)-1-methylureido)-4-hydroxypentyl isoquinolin-3-ylcarbamate in MeOH (15 mL) at 0° C. was added conc. HCl (12 N, 16 mL, 192.4 mmol) dropwise. The mixture was stirred for 30 min and concentrated. The residue was dissolved in 50 mL H2O. Aqueous NaOH solution (1 N) was added to adjusted the PH to 3˜4. EtOAc (50 mL) was then added. The mixture was stirred at RT for 1 h. The white solid was then filtered and washed with H2O and EtOAc and dried under high vacuum to give (2S,4R)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-hydroxy-5-(phosphonooxy)pentyl isoquinolin-3-ylcarbamate (2.85 g) as a white powder (4.95 g, 89% for 2 steps). LRMS (M−H+) m/z 567.5
Reaction SMILES: N[C:2]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[O:7][C:6]1=[O:25].N(OC(C)(C)C)=O.[I:42]I>C(Cl)(Cl)Cl.CCOC(C)=O>[F:22][C:21]([F:24])([F:23])[C:13]1[CH:12]=[C:11]([C@H:8]2[O:7][C:6](=[O:25])[N:5]([CH2:4][C:3]3[CH:26]=[C:27]([O:30][C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:29][C:2]=3[I:42])[C@H:9]2[CH3:10])[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=1
Reactant: II
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1N
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1I
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (582 mg, 1.16 mmol) in CHCl3 (35 mL) was added t-butyl nitrite (275 μL, 2.32 mmol). After 10 minutes, I2 (736 mg, 2.9 mmol) was added. The reaction was stirred at room temperature for 30 minutes, and then heated to 65° C. for 2 hours. The reaction was then cooled to room temperature, diluted with EtOAc (150 mL) and washed with aqueous NaHSO3, water, brine, saturated NaHCO3, and brine (50 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (2 to 15% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.30 (15% EtOAc/hexanes). LCMS=614.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89-7.91 (m, 2H), 7.79 (s, 2H), 7.23 (m, 1H), 6.95 (m, 1H), 5.75 (d, J=8.0 Hz, 1H), 4.81 (d, J=15.8 Hz, 1H), 4.32 (d, J=15.8 Hz, 1H), 4.07 (m, 1H), 0.78 (d, J=6.6 Hz, 3H).
Reaction SMILES: [N:1]1([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20]1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:19]3[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20]3)=[O:16])=[CH:17][CH:18]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O[C@@H]1CCNC1
Reactant: O=C(O)c1ccc(-n2cnc3ccccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2cnc3ccccc32)cc1)N1CC[C@@H](O)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 64 %

Procedure:
A solution of 4-(1H-benzimidazol-1-yl)benzoic acid (2.88 g, 12.09 mmol) in DMF is treated with (3R)-pyrrolidin-3-ol (1.106 g, 12.69 mmol), 1-ethyl-3(3-dimethylaminopropyl)carbodiimide (2.78 g, 14.51 mmol) and N-hydroxybenzotriazole (1.89, 13.29 mmol), stirred at 80° C. for 12 hours and concentrated in vacuo. The resultant residue is dissolved in dichloromethane, washed sequentially with water and saturated NaCl, dried over MgSO4 and concentrated in vacuo to give a crude oil. Purification of this oil by flash column chromatography (silica, methanol:CH2Cl2 5:95) provides the title product as a white solid, 2.38 g (64% yield), identified by NMR and mass spectral analyses. (MS [308.4 m/e (M+H)].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[NH:12][NH2:13]>C(O)C>[N:8]1[CH:9]=[CH:10][C:5]([C:1](=[N:13][NH:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccncc1
Reactant: CCOC(=O)NN
Solvent: CCO
Product: CCOC(=O)NN=C(CC)c1ccncc1
Temperature: 25 °C
Yield: 49 %

Procedure:
A solution of 4.05 gm (0.03 mole) of 4-propionylpyridine, 3.12 gm (0.03 mole) of ethyl carbazate and 100 ml of absolute ethanol is refluxed 6 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point. The mixture is cooled at room temperature and then chilled in the refrigerator to give crystals which are collected, washed with Skellysolve B and dried to yield 3.25 gm (49%) of the title compound having a melting point of 147.1° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.Cl.[NH2:14][OH:15].[OH-].[Na+]>O1CCCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[N:14][OH:15])=[CH:8][CH:9]=2)[CH2:4][O:3]1
Reactant: NO
Reactant: O=Cc1ccc2c(c1)COC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1OCc2cc(C=NO)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Oxo-1,3-dihydroisobenzofuran-5-carbaldehyde (2.01 g, 12.4 mmol) obtained from Example 4-(3) was suspended in tetrahydrofuran (50 ml), and after the suspension was cooled to 0° C., hydroxylamine hydrochloride (1.04 g, 14.9 mmol) in an aqueous solution of sodium hydroxide (1.0N; 14.8 ml, 14.8 mmol) was added thereto. The resulting mixture was stirred at room temperature for 1 hour, and then concentrated to one third of the volume under reduced pressure. To the concentrated solution was added water, and the product was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure to give crude 1-oxo-1,3-dihydroisobenzofuran-5-carbaldehyde oxime as a solid. The crude product was dissolved in tetrahydrofuran (50 ml), and the solution was cooled to 0° C., then triethylamine (3.04 g, 30 mmol) and anhydrous trifluoroacetic acid (3.13 g, 14.9 mmol) were added thereto. The resulting mixture was stirred at the same temperature for 30 minutes, and then warmed to room temperature followed by stirring for 30 minutes more. The reaction mixture was cooled again to 0° C., and a saturated aqueous solution of sodium hydrogen carbonate was added thereto. The reaction product was extracted with ethyl acetate, and the combined organic layers were washed with a saturated aqueous solution of sodium chloride. The extract was concentrated under reduced pressure to give a solid residue. The residue was subjected to chromatography on a silica gel (150 g) column (eluent; ethyl acetate:dichloromethane=0:1˜1:10) to afford the title compound (1.57 g, 79% yield) as a solid (mp. 200-201° C.).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Fc1ccccc1CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2F)CCCC1=O
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
40% Methanolic Triton B (2.82 mL, 6.2 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (1.27 g, 5.22 mM) in 10 mL of DMF at 25° C. After 5 minutes, 2-fluorobenzyl bromide (1.19 g, 6.2 mM) was added and the resultant mixture stirred at room temperature for 17 days. The mixture was diluted with ethyl acetate, washed five times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 1.00 g (55%) of the 9-[(2-fluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan foam. 1H NMR (DMSO-d6) δ7.7 (dd, 1H, J=1 and 8 Hz), 7.4-7.2 (m, 4H), 7.1 (t, 1H, J=8 Hz), 6.7 (t, 1H, J=8 Hz), 5.65 (s, 2H), 3.8 (s, 3H), 3.0 (t, 2H, J=6 Hz), 2.45 (t, 2H, J=6 Hz), and 2.1 (m, 2H). IR (CDCl3, cm−1) 3050, 2950, 1725, 1652, 1464, 1441, 1288 and 1120. MS (ES) m/e 350, 352.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:33]1[C:38]([C:39]#[N:40])=[CH:37][N:36]=[CH:35][CH:34]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:33]4[CH:34]=[CH:35][N:36]=[CH:37][C:38]=4[C:39]#[N:40])[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Reactant: N#Cc1cnccc1Br
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccncc4C#N)ccc3O2)CC1

Procedure:
The title compound is prepared from 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester and 4-bromo-nicotinonitrile following a procedure analogous to that described in Example 1. LC (method 6): tR=1.31 min; Mass spectrum (ESI+): m/z=406 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:23][S:24]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25].[C:33]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:33]1([N:30]2[CH2:29][CH2:28][CH:27]([S:24]([CH2:23][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]5[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=5)=[O:12])=[CH:21][CH:22]=4)[O:6][C:2]=3[CH3:1])(=[O:25])=[O:26])[CH2:32][CH2:31]2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCNCC1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A solution of 4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide (300 mg, 0.66 mmol, 1.00 equiv), cyclopentanone (84 mg, 1.00 mmol, 1.51 equiv) and acetic acid (60 mg, 1.00 mmol, 1.51 equiv) in 1,2-dichloroethane (10 mL) was stirred at room temperature for 4 h. Sodium triacetoxyborohydride (420 mg, 1.98 mmol, 3.00 equiv) was added and the resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum and the residue was eluted with water/acetonitrile (95:5-20:80) on a C18 column to give 240 mg (70%) of 4-[4-[(1-cyclopentylpiperidine-4-sulfonyl)methyl]-5-methyl-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide as a colorless solid. LC-MS- (ES, m/z): 523 [M+H]+, 262; 1HNMR (400 MHz, CD3OD, ppm) δ 8.60 (s, 1H), 8.48 (d, 1H), 8.11 (d, 2H), 7.99 (d, 2H), 7.89 (d, 1H), 7.45 (m, 1H), 4.65 (s, 2H), 4.46 (s, 2H), 3.49 (d, 2H), 3.37 (t, 1H), 3.02 (t, 1H), 2.58-2.55 (m, 2H), 2.51 (s, 3H), 2.37 (d, 2H), 2.06-1.96 (m, 4H), 1.83-1.70 (m, 2H), 1.69-1.51 (m, 4H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(O)=O.S(=O)(=O)(O)O.[CH2:17]=[CH:18][CH2:19][CH3:20].C=C(C)C>CCCCCCC>[C:1]([O:8][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: C=CCC
Reactant: CC(=O)CCC(=O)O
Agent: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: O=CO
Solvent: CCCCCCC
Product: CCCCOC(=O)CCC(C)=O
Temperature: 150 °C

Procedure:
A 5 cc autoclave is charged with 1 cc of heptane and 1 cc of an aqueous solution containing 2 mmoles of levulinic acid and 2 mmoles of formic acid. 5 wt. % sulfuric acid is added as a catalyst. The reactor is pressurized to 0.69 MPa with 1-butene and heated to 150° C. for 0.5 hours while maintaining a constant pressure of isobutene. After cooling, the organic phase is separated. A mixture of butyl formate and butyl levulinate is formed as product.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[C:24]1[C:33]2[N:32]=[CH:31][CH:30]=[N:29][C:28]=2[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1>>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:34]([C:27]3[C:28]4[N:29]=[CH:30][CH:31]=[N:32][C:33]=4[C:24]([C:18]4[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=4[CH3:16])=[CH:25][CH:26]=3)=[O:35])=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)c2nccnc12
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Product: CCN1CCN(c2ccc(NC(=O)c3ccc(-c4c(C)cccc4C)c4nccnc34)cc2)CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 4-(4-ethylpiperazin-1-yl)-aniline (Step 1.9) and 8-(2,6-dimethyl-phenyl)-quinoxaline-5-carbox-ylic acid (Example 71). Title compound: ESI-MS: 466.2 [M+H]+; tR=3.67 min (System 3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:13]([CH3:12])[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 21 %

Procedure:
3,4-Dichlorobenzoyl chloride (60 mg, 0.29 mmol, CAS RN 2905-60-4) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (45 mg, 0.23 mmol, example 1, intermediate a) and DIPEA (79 μL, 0.45 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the product as a waxy solid (18 mg, 21%). MS (ESI): m/z=371.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1Cl.[CH3:15][SH:16].[OH-].[Na+]>CS(C)=O.O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[S:16][CH3:15]
Reactant: CS
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a stirred solution containing 45.1 g (0.20 mole) of 3-(trifluoromethyl)-4-chloronitrobenzene and 15 g (0.30 mole) of methyl mercaptan in 150 ml of DMSO was added dropwise at ambient temperature a solution containing 8.0 g (0.20 mole) of sodium hydroxide in 20 ml of water. This addition was exothermic to 60° C. After one hour, the reaction mixture was poured into ice water. The product was filtered and dried to give 45.0 g (95%) of yellow solid; m.p. 50° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I.[H-].[Na+].Cl>O.O1CCCC1>[CH2:1]([O:8][C:9]([N:11]([CH3:24])[CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: COC(=O)c1ccc(CCNC(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCc1ccc(C(=O)O)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Methyl 4-(2-(benzyloxycarbonylamino)ethyl)benzoate ((3.2 g, 10.2 mmol) was added to tetrahydrofuran (34 mL) and reacted with methyl iodide (3.8 mL, 61.2 mmol), then sodium hydride (2.0 g, 51 mmol) was added batch-wise and the reaction mixture was stirred for 3 h at room temperature, and then water (1 mL) was added. The mixture was stirred at room temperature for 1 h, adjusted to pH=3 with 1N hydrochloric acid and the mixture was extracted by ethyl acetate (50 mL×3), washed by water and evaporated the solvent. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 10:1 to 2:1, acetic acid was added) to obtain 4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)benzoic acid (2.3 g, yield 72%) as yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.79-2.85 (m, 5H), 3.49 (m, 2H), 4.95-5.04 (t, J=19 Hz, 2H), 7.24-7.37 (m, 7H), 7.83-7.86 (m, 2H), 12.8 (s, 1H); LC-MS (ESI) m/z: 314 (M+1)+.