Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([Cl:12])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]>C(COC)OC.O>[CH3:1][S:2][C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([Cl:12])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1cc(N)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a suspension of 18.9 g (0.27 mol) of sodium thiomethoxide in 200 ml of dimethoxyethane, with stirring at room temperature, are added portionwise 41.4 g (0.2 mol) of 2,5-dichloro-4-aminonitrobenzene, allowing the temperature to rise to 50°-55° C. and maintaining this temperature for 1/2 hour after the addition is complete. The reaction medium is poured onto 2 liters of ice-water. The crystallized precipitate is drained, re-slurried in water and vacuum-dried at 40° C. over phosphorus pentoxide.
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[C:8]([O:16][CH3:17])=[CH:9][C:10]([O:14][CH3:15])=[C:11]([NH2:13])[CH:12]=1.N([O-])=O.[Na+].[N-:22]=[N+:23]=[N-].[Na+]>O>[N:13]([C:11]1[CH:12]=[C:7]([Cl:6])[C:8]([O:16][CH3:17])=[CH:9][C:10]=1[O:14][CH3:15])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(OC)c(Cl)cc1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(OC)c(N=[N+]=[N-])cc1Cl
Temperature: 0 °C

Procedure:
To a solution of concentrated H2SO4 (5 mL) in water (15 mL), 5-chloro-2,4-dimethoxy-phenylamine (3 g, 16 mmol) was added, resulting a deep purple suspension. More water (15 mL) was then added and the mixture was cooled and stirred vigorously at 0° C. in an ice-salt bath. A solution of sodium nitrite (1.2 g, 17.4 mmol) in water (5 mL) was added slowly and a brown solution was obtained. This solution was stirred at this temperature for an hour. After that, a solution of sodium azide (1.2 g, 18.5 mmol) in water (10 mL) was followed and the solution turned grey. This solution was then stirred for an hour. The grey precipitations (1.0 g, 30%) formed were collected, washed with water and dried. Yellow solids formed in the filtrate were also collected, washed and dried. The second crop (1.47 g, 43%) turned to light grey quickly.
Reaction SMILES: [CH2:1]1[CH:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]2=O)[C:3](=[N:15]O)[CH2:2]1.[OH-:17].[Na+]>C(OCC)(=O)C>[NH:15]1[C:3](=[O:17])[CH2:2][CH2:1][C:13]2[N:4]=[CH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]1=2
Reactant: O=C1c2ccccc2CN2C(=NO)CCC12
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1CCc2ncc3ccccc3c2N1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 300 g of vigorously stirred polyphosphoric acid warmed to 115° C., 10 g of 1,10a-dihydropyrrolo[1,2-b]isoquinoline-3,10[2H,5H]-dione oxime was added. The mixture was held at this bath temperature for 10 minutes. The internal temperature rose to 135°-140° C. The mixture was then poured into 1500 ml of ice water, and the mixture was basified with 50% NaOH to about pH=8 and the resultant crystalline precipitate was collected to give 7.14 g of crude product. Chromatography on a silica gel column, using ethyl acetate gave 4.8 g of pure product, m.p. 225° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][C:7]1[C:12]2[CH:13]=[CH:14][O:15][C:11]=2[C:10]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:9][CH:8]=1.[H][H]>CO.[Pd]>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[CH2:6][C:7]1[C:12]2[CH2:13][CH2:14][O:15][C:11]=2[C:10]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Nc1ccc(CC2=NCCN2)c2ccoc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(CC2=NCCN2)c2c1OCC2

Procedure:
A mixture of N-[4-(4,5-dihydro-1H-imidazol-2-ylmethyl)-benzofuran-7-yl]-methanesulfonamide (44 mg, 0.13 mmoles) and 10% Pd-C (pinch) in methanol (5 mL) was stirred under hydrogen which was supplied by a hydrogen filled balloon, at room temperature for 17 days. The catalyst was removed by filtration through celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 10% to 12% methanol in dichloromethane with 0.1% ammonium hydroxide to give N-[4-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2,3-dihydro-benzofuran-7-yl]-methanesulfonamide as a solid which was further purified by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) M+H 296. The following representative compounds were synthesized similarly as shown above. Additional compounds prepared according to the procedure of Example 1 are shown in Table 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](SC)=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:16].O.[NH2:18][NH2:19]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:18][NH2:19])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:16]
Reactant: NN
Reactant: CSc1ncc(-c2ccc(Br)c(F)c2)nn1
Solvent: CCO
Solvent: O
Product: NNc1ncc(-c2ccc(Br)c(F)c2)nn1
Temperature: 90 °C
Yield: 77.7 %

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-3-(methylthio)-1,2,4-triazine (1.15 g, 0.00383 mol) and hydrazine hydrate (0.74 mL, 0.015 mol) in ethanol (50 mL) was heated at 90° C. for 20 h. After cooling, the formed precipitate was collected by filtration, and dried in-vacuo to afford the desired product (0.845 g, 77.6%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][C:7]([Cl:12])=[N:6][C:5]=2[NH:4][CH:3]=1.[Li][CH2:14]CCC.CI>C1COCC1>[Cl:12][C:7]1[N:8]=[C:9]([Cl:11])[C:10]2[C:2]([CH3:14])=[CH:3][NH:4][C:5]=2[N:6]=1
Reactant: [Li]CCCC
Reactant: Clc1nc(Cl)c2c(Br)c[nH]c2n1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c[nH]c2nc(Cl)nc(Cl)c12
Temperature: -78 °C

Procedure:
1.4 g 5-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (4) (5.2 mmol) was dissolved in 200 mL of THF. After cooling to −78° C., 9.75 mL of BuLi (1.6M solution in Hexanes, 15.6 mmol) was slowly added over a period of 30 minutes, then stirred for 30 minutes at −78° C. before 396 uL of MeI (6.24 mmol) was dropwise added into the reaction mixture over a period of one hour. The reaction mixture was stirred at −78° C. for one more hour and quenched by adding 20 mL of saturated aqueous NH4Cl solution at this temperature. The reaction mixture was then partitioned between 100 mL of saturated NaHCO3 and 100 mL of EtOAc. The organic layer was separated and the aqueous layer is extracted with EtOAc (3×100 mL). Combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the crude title compound which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[CH:7]2)[CH3:2].[CH2:14](Br)[C:15]#[CH:16].[I-:18].[Na+]>C(#N)C>[I-:18].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N+:9]([CH2:16][C:15]#[CH:14])[CH:8]=[CH:7]2)[CH3:2]
Reactant: C#CCBr
Reactant: CCOc1ccc2cnccc2c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C#CC[n+]1ccc2cc(OCC)ccc2c1

Procedure:
6-Ethoxyisoquinoline (500 mg.), propargyl bromide (500 mg.) and sodium iodide (300 mg.) were heated under reflux in acetonitrile (30 ml) for 5 hrs. The mixture was evaporated to dryness, the residue taken up in hot water (5 ml) and a saturated aqueous solution (5 ml) of sodium iodide added to the cooled filtrate. The solid that precipitated was recrystallised from isopropanol/ether, m.p. 121°-123°.
Reaction SMILES: [O:1]([NH2:3])[CH3:2].[C:4]1([CH3:14])[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1.O>N1C=CC=CC=1>[CH3:2][O:1][NH:3][S:10]([C:7]1[CH:8]=[CH:9][C:4]([CH3:14])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CON
Solvent: O
Solvent: c1ccncc1
Product: CONS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
Methoxylamine (9.00 g (108 mmol) was suspended in pyridine (30.0 ml). To this, under cooling with ice and with stirring, p-toluenesulfonyl chloride (19.07 g (100 mmol)) was added and the mixture was stirred under cooling with ice for 30 minutes and at room temperature for 2 hours. Water (200.0 ml) was added to the reaction mixture to bring about separation of crystals. After 30 minutes' stirring, the crystals were filtered and washed to give 20.26 g (99%) of N-methoxy-p-toluenesulfonamide as white crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:19])[N:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[F:18])=[O:5])C.[Li+].[OH-]>O1CCCC1>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[N:9]=[N:8][N:7]([CH3:19])[C:6]=2[C:4]([OH:5])=[O:3])=[C:12]([F:18])[CH:13]=1
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2F)nnn1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccc(Br)cc2F)c1C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.9 %

Procedure:
In a 250 mL round-bottomed flask, 5-(4-bromo-2-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazole-4-carboxylic acid ethyl ester (291 mg, 887 μmol) was combined with tetrahydrofuran (18 mL) to give a colorless solution. 1M LiOH (9 mL, 9.00 mmol, Eq: 10.1) was added and the reaction was stirred at 25° C. for 15 h. The crude reaction mixture was concentrated in vacuo and acidified with 10 mL of 1M HCl. The reaction was diluted with EtOAc and the organic layer was washed with H2O (1×20 mL) and saturated NaCl (1×20 mL), dried over Na2SO4 and concentrated in vacuo. The white powder was dried under vacuum to afford 266 mg (100%) of the desired product. (M−H)−=297.8 and 299.9 (m/e).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:26])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][CH:7]=[CH:6][CH:5]=2.N1C=CC=CC=1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>ClCCl>[C:33]([O:1][C:2]1[C:3](=[O:26])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:36])[CH2:34][CH3:35]
Reactant: CCC(=O)Cl
Reactant: C[Si](C)(C)CCCCCCCCCC1=C(O)C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)OC1=C(CCCCCCCCC[Si](C)(C)C)C(=O)c2ccccc2C1=O
Reaction time: 0.05 h

Procedure:
To a stirred solution of 2-hydroxy-3-(9-trimethylsilylnonyl)-1,4-naphthoquinone, Example 12, (100 mg, 0.27 mmol) in dry dichloromethane (10 ml) at room temperature was added pyridine (0.5 ml) and, after 3 minutes, propanoyl chloride (62 mg, 0.67 mmol). The reaction was stirred for 2 h before diluting with dichloromethane (50 ml), washing with water (2×30 ml), dilute hydrocholic acid (30 ml), saturated sodium chloride solution (30 ml) and dried (MgSO4). Filtration and evaporation of the solvent under reduced pressure and chromatography, eluent hexane/ether, gave 2-propanoyloxy-3-(9-trimethylsilylnonyl)-1,4-naphthoquinone (112 mg). m. pt. 41-43° C. NMR peaks at: 184.6, 178.2, 151.2, 139.8, 134.0, 133.7, 132.1, 130.9, 126.7, 126.5, 33.6, 29.7, 29.4, 29.4, 29.3, 29.3, 28.5, 24.3, 23.9, 16.7, -1.6; 171.6, 27.3, 9.1 (COCH2CH3).
Reaction SMILES: O[CH:2]([CH3:14])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13].O=S(Cl)[Cl:17]>O1CCOCC1>[Cl:17][CH:2]([CH3:14])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13]
Reactant: CC(O)Cn1c(=O)[nH]c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CC(Cl)Cn1c(=O)[nH]c2ccccc21

Procedure:
13.2 gm of N-(2-hydroxy-propyl)-benzimidazolone were dissolved in 150 ml of dioxane, and after addition of 8 ml of SOCl2 the mixture was refluxed for one hour. After evaporation in vacuo, the residue was dissolved in ethyl acetate, and the solution was washed with a sodium bicarbonate solution and water, and dried over Na2SO4. After distilling off the solvent, 13.4 gm of N-(2-chloro-propyl)-benzimidazolone were obtained.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[N:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])[O:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:29][O:30][C:31](=[O:37])[CH2:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][S:33]([CH2:32][C:31]([O:30][CH3:29])=[O:37])(=[O:35])=[O:34])[N:16]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4N)no2)cc1C#N
Reactant: COC(=O)CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)N[C@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Prepared using General Procedure 16: To a stirred solution of (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 50 (0.36 g, 1.0 mmol) in DCM (5 mL) was added methyl-2-(chlorosulfonyl)acetate (112 mg, 0.6 mmol). After 0.5 h, the crude reaction was partitioned between DCM and saturated NaHCO3. The organic layer was dried over MgSO4, concentrated, and purified by column chromatography (EA/hexanes) to give 0.21 g (42%) of (S)-methyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate 72. LCMS-ESI (m/z) calculated for C24H24N4O6S: 496.1; found 519.1 [M+Na]+, tR=3.71 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.1 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.13 (d, J=7.7 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 5.20-5.00 (m, 2H), 4.78 (hept, J=6.2 Hz, 1H), 4.16 (d, J=14.9 Hz, 1H), 4.08 (d, J=14.9 Hz, 1H), 3.82 (s, 3H), 3.51 (ddd, J=17.4, 8.9, 3.5 Hz, 1H), 3.28-3.11 (m, 1H), 2.71 (dtd, J=11.3, 8.1, 3.6 Hz, 1H), 2.16-2.02 (m, 1H), 1.46 (d, J=6.1 Hz, 6H). (R)-methyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate was synthesized in an analogous fashion from (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49.
Reaction SMILES: C([O:5][C:6](=[O:73])[C@H:7]([CH2:64][CH2:65][C:66]([O:68]C(C)(C)C)=[O:67])[NH:8][C:9](=[O:63])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:62])[CH2:19][CH2:20][S:21][CH2:22][CH:23]([O:44][C:45](=[O:61])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[CH:24]([O:26][C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH3:25])=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:45]([O:44][CH:23]([CH:24]([O:26][C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH3:25])[CH2:22][S:21][CH2:20][CH2:19][C:18]([NH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C@H:7]([C:6]([OH:73])=[O:5])[CH2:64][CH2:65][C:66]([OH:68])=[O:67])=[O:63])=[CH:11][CH:12]=1)=[O:62])(=[O:61])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(C)C(CSCCC(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)OC(C)C(CSCCC(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A solution of 4-[6,7-bis(palmitoyloxy)-4-thiaoctanoylaminomethyl]benzoyl-glutamic acid di-t-butyl ester as obtained in Example 75 (574 mg) in methylene chloride (4 ml)-trifiuoroacetic acid (5 ml) was stirred at room temperature for 4 hours, after which the solvent was distilled off under reduced pressure. The residue was recrystallized from methanolwater to yield the title compound (505 mg, yield 99%) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([Si](CCC)(CCC)CCC)[CH:6]=[CH:5][C:4]=2[C:3]=1[C:21]([OH:23])=O.F[P-](F)(F)(F)(F)F.[N:31]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O.N.O>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:21]([NH2:31])=[O:23]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCC[Si](CCC)(CCC)n1ccc2c(C(=O)O)c(F)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1c(F)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A mixture of 5-fluoro-1-(tripropylsilyl)-1H-indole-4-carboxylic acid (500 mg, 1.49 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (851 mg, 2.24 mmol), and TEA (452 mg, 4.48 mmol) in DMF (5 mL) was stirred at RT for 1 hour. To the mixture was added ammonia water (1 mL), followed by stirring at RT overnight. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography using petroleum ether/EtOAc (2:1) as eluting solvents to afford 5-fluoro-1H-indole-4-carboxamide as a white solid (260 mg, 52.2%). MS (ESI): m/z=179.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6][N:5]1[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19].[H][H]>[Pd].CO>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19]
Reactant: COCC1CN(Cc2ccccc2)CCN1C(=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCC1CNCCN1C(=O)C(F)(F)F
Yield: 92 %

Procedure:
A mixture of 9.2 parts of 2-(methoxymethyl)-4-(phenylmethyl)-1-(trifluoroacetyl)piperazine and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 6.05 parts (92%) of 2-(methoxymethyl)-1-(trifluoroacetyl)piperazine as a residue (intermediate 59).
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([N:8]([CH3:17])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCC1CCNCC1)Cc1ccccc1
Reactant: Brc1ccncc1
Agent: Br
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCC1CCN(c2ccncc2)CC1)Cc1ccccc1
Reaction time: 16 h
Yield: 56 %

Procedure:
N-Benzyl-N-methyl-2-(piperidin-4-yl)ethanamine (600 mg, 2.58 mmol, 1 eq) and 4-bromo-pyridine HBr (553 mg, 2.84 mmol, 1.1 eq) were dissolved in n-butanol (15 ml); DIPEA (2.34 ml, 12.9 mmol, 5 eq) was added, and refluxing was carried out for 16 h. After monitoring by thin-layer chromatography, the reaction mixture was concentrated and the residue was purified by column chromatography (Alox 5-7% MeOH in dichloromethane). Yield: 56% (450 mg, 1.45 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])=[CH:4][C:3]=1I.[CH3:14][Si:15]([C:18]#[C:19][Si](C)(C)C)([CH3:17])[CH3:16].C([O-])(O)=O.[Na+]>CC#N>[CH3:12][NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:18]([Si:15]([CH3:17])([CH3:16])[CH3:14])=[CH:19]2
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Reactant: CNC(=O)Cc1ccc(N)c(I)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CNC(=O)Cc1ccc2[nH]c([Si](C)(C)C)cc2c1
Yield: 38.7 %

Procedure:
4-Amino-3-iodo-N-methyl-benzeneacetamide (7) (7.26 g, 0.025 mol), bis(trimethylsilyl) acetylene (8.52 g, 0.05 mol) and tetrakistriphenylphosphine Pd(O) (2.89 g, 0.0025 mol) were dissolved in CH3CN (400 mL) followed by the addition of saturated aqueous NaHCO3 (30 mL). The mixture was heated at reflux for 24 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic phase was extracted with brine, dried over MgSO4, filtered and concentrated in vacuo. Silica gel chromatography (50-100% EtOAc gradient in hexane) of the concentrate afforded the product (8) (2.52 g, 38.8%) as a yellow viscous oil.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (6.70 g, 28.2 mmol) in CH2Cl2 (100 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 1-chloro-4-((E)-2-nitro-vinyl)-benzene (4.97 g, 27.1 mmol) and trifluoroacetic acid (0.31 g, 2.7 mmol) in CH2Cl2 (150 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:4) afforded 6.75 g (79%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:5]=[CH:6][CH:7]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To the suspension of 4-(3-fluoro-phenyl)-1H-indole (1.40 g, 6.63 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (81 mL) was added pyridinium tribromide (90% purity from Aldrich, 7.07 g, 19.88 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (30 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (1.34 g, 89%) as a tan solid.
Reaction SMILES: [O:1]=[C:2]([NH:28][O:29]C1CCCCO1)[CH:3]([NH:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:29][NH:28][C:2]([CH:3]([NH:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:13]=1)(=[O:6])=[O:7])=[O:1]
Reactant: CCCCC(=O)NC(CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CCCCC(=O)NC(CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To a solution of the title compound of Example 11f (500 mg, 0.96 mmol) in methanol (20 mL) was added p-toluenesulfonic acid, monohydrate (40 mg, 0.21 mmol). After stirring at room temperature for 2 hours, the solution was concentrated. Purification by chromatography (6:94 MeOH/CHCl3) yielded the title compound as a light beige solid (170 mg, 40%): Anal. Calcd. for C20H24N2O5S2.0.5 H2O: C, 53.91; H, 5.66; N, 6.29; S, 14.39. Found: C, 53.98; H, 5.44; N, 6.20; S, 14.47.