Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:14])[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([F:15])[C:3]=1[CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCOC(C)=O.Cl.Cl.[CH2:53]([O:60][C:61](=[O:73])[NH:62][C:63]([C:65]1[CH:70]=[CH:69][C:68]([CH2:71][NH2:72])=[CH:67][CH:66]=1)=[NH:64])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C=O)C>[CH2:53]([O:60][C:61](=[O:73])[NH:62][C:63]([C:65]1[CH:66]=[CH:67][C:68]([CH2:71][NH:72][C:17](=[O:19])[CH:16]([C:3]2[C:4]([F:15])=[CH:5][C:6]([C:8](=[O:14])[NH:9][CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:7][C:2]=2[F:1])[O:20][CH2:21][CH3:22])=[CH:69][CH:70]=1)=[NH:64])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Reactant: CCOC(C(=O)O)c1c(F)cc(C(=O)NCC(C)C)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(C(=O)NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1)c1c(F)cc(C(=O)NCC(C)C)cc1F
Yield: 22.9 %

Procedure:
(RS)-(2,6-Difluoro-4-isobutylcarbamoyl-phenyl)-ethoxy-acetic acid (71 mg) was dissolved in DMF (3.5 ml) and [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester dihydrochloride [Prepared according to Ch. Lila, Ph. Gloanec, L. Cadet, Y. Hervé, J. Fournier, F. Leborgne, T. J. Verbeuren, G. De Nanteuil, Synthetic Communications 1998, 28, 23, 4419–4429] (88 mg), disopropylamine (114 mg) and 2-(1H-benzotriazole-1-yl) 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (80 mg) were subsequently added. After 30 min stirring at rt AcOEt (10 ml) was added and the organic layer was washed with 1 N HCl (2×10 ml), H2O (10 ml) and brine. The aqueous layers were extracted with more AcOEt (10 ml). After drying (MgSO4) the solvent was evaporated and the crude product was purified by HPLC to obtain 30 mg (23%) of (RS)-[(4-{[2-(2,6-difluoro-4-isobutylcarbamoyl-phenyl)-2-ethoxy-acetylamino]-methyl}-phenyl)-imino-methyl]-carbamic acid benzyl ester. White solid. MS 581.4 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][S-:13].[Na+]>CC(N(C)C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[S:13][CH3:12]
Reactant: C[S-]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CSc1ccc(C(C)=O)cc1Br
Temperature: 120 °C

Procedure:
The 1-(3-bromo-4-fluorophenyl)ethanone (2.00 g, 9.20 mmol) and sodium thiomethoxide (0.710 g, 10.1 mmol) was dissolved in dimethylacetamide (4.6 mL) and the slurry was heated at 120° C. in a microwave reactor for 1 h. The reaction mixture was diluted with water (30 mL) and the mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (1×75 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica gel, 0 to 75% EtOAc:hexanes) to give 1-(3-bromo-4-(methylthio)phenyl)ethanone. Mass Spectrum (ESI) m/e=245.1 (M+1).
Reaction SMILES: FC1C=CC(CN)=CC=1.[CH3:10][C:11]1[O:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36](O)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36]([NH:16][CH2:15][C:14]3[O:17][C:11]([CH3:10])=[CH:12][CH:13]=3)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: Cc1ccc(CN)o1
Agent: NCc1ccc(F)cc1
Product: Cc1ccc(CNC(=O)c2sc(N3CCN(Cc4ccccc4)C3=O)nc2C)o1
Yield: 29 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 5-methylfurfurylamine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 29% yield: mp 138-139° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.36-7.25 (m, 5H), 6.10 (d, J=2.7 Hz, 1H), 5.90-5.86 (m, 2H), 4.50-4.44 (m, 4H), 4.04 (t, J=8.1 Hz, 2H), 3.43 (t, J=8.1 Hz, 2H), 2.58 (s, 3H), 2.24 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.1, 157.3, 155.4, 153.1, 152.1, 148.9, 135.5, 128.8, 128.3, 128.0, 117.1, 108.5, 106.3, 47.9, 42.0, 41.6, 37.0, 17.1, 13.5; MS (ES+) m/z 411.3 (M+1).
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:20][CH2:19][C@@H:18]([N:21]2[CH:28]=[CH:27][C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:17][C@@H:16]1[OH:29])([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].C(O)(=O)C.[CH2:34]([NH2:37])[CH:35]=[CH2:36].C(O)(=O)C>C([O-])(=O)C.[Na+].O>[P:1]([O:13][CH2:14][C@H:15]1[O:20][CH2:19][C@@H:18]([N:21]2[CH:28]=[C:27]([CH2:36][CH:35]=[CH:34][NH2:37])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:17][C@@H:16]1[OH:29])([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: C=CCN
Reactant: O=c1ccn([C@@H]2CO[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)C2)c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC=CCc1cn([C@@H]2CO[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)C2)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
100 mg (0.19 mmol)of 1,5-Anhydro-2-(uracil-1yl)-2,3-dideoxy-D-arabino-hexitol 6 triphosphate and 106 mg (0.33 mmol) mercury II acetate were dissolved in 5 ml 0.1 M sodium acetate buffer pH5 The mixture was stirred for 4 h at 50° C. after cooling to room temperature the mixture was diluted with 40 ml water. A freshly prepared allylamine acetate solution. (0.77 ml (13 mmol) were neutralized with 4M acetic acid) and 150 mg (1.5 mmol) dipotassium tetrachloropalladinate were added and the mixture was stirred for 24 h at room temperature. The reaction mixture was filtered through a 0.45 μm membrane filter and the filtrate was applied on a DEAE-Sephadex column and it was eluated with a gradient from 0.1-1 M Trieethylammoniumbicarbonate pH8 monitoring at 260 nm. The major UV peak was collected (Ninhydrine reaction positive) and further purified by reversed phase chromatography with a gradient from buffer 100% A: 0.1M triethylammonium acetate pH 8.0 to 100% buffer B: 0.1 M triethylammonium acetate/Acetonitril 1:1 monitoring at 260 nm on a RP 18 Hypersil column) The fractions containing the aminoallyl triphosphate were collected and evaporated under vacuum. The presence of the aminogroup was verified by ninhydrine reaction Excess triethylammonium-acetate was removed by several coevaporations with water. Yield 80 mg
Reaction SMILES: O[CH:2]1[CH2:9][CH2:8][C:5]2([CH2:7][CH2:6]2)[CH2:4][CH:3]1[C:10]#[N:11].CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.O>[CH2:6]1[C:5]2([CH2:8][CH2:9][CH:2]=[C:3]([C:10]#[N:11])[CH2:4]2)[CH2:7]1
Reactant: N#CC1CC2(CCC1O)CC2
Agent: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#CC1=CCCC2(CC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-hydroxyspiro[2.5]octane-5-carbonitrile (110 mg, 0.73 mmol) in DCM (3.6 mL) was added DIPEA (190 mg, 1.4 mmol) followed by the dropwise addition of methanesulfonyl chloride (92 mg, 0.80 mmol). The resulting mixture was stirred at ambient temperature for 3 hours then DBU was added and stirring continued for 16 hours. The mixture was carefully diluted with water and extracted with EtOAc (2×). The combined organic extracts were washed with 1N aqueous HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound. The residue was carried forward without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15].Cl.[Cl:21][C:22]1[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][N:23]=1>C(Cl)Cl>[Cl:21][C:22]1[CH2:26][C:25]([CH3:28])([CH3:27])[N:24]([C:14]([C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([F:10])[CH:12]=2)=[O:15])[N:23]=1
Reactant: CC1(C)CC(Cl)=NN1
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CC(Cl)=NN1C(=O)c1cccc(F)c1
Temperature: 0 °C
Yield: 37 %

Procedure:
A 250 mL round bottom flask equipped with a stir bar and nitrogen inlet was charged with dry CH2Cl2 (100 mL), Hunigs base (7.8 mL, 45 mmol) DMAP (5 mg) and 3-fluorobenzoyl chloride (1.8 mL. 15 mmol). The mixture was cooled to 0° C. To this mixture was added portionwise, 3-chloro-5,5-dimethyl-4,5-dihydro-1H-pyrazole.Hydrochloride (1.68 g, 10 mmol) and the reaction was allowed to warm to RT overnight. LC-MS showed consumption of SM. The reaction was added to water (100 mL), the phases were separated and the organic phase was washed with NaHCO3 (100 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The material was purified by chromatography using a 40 g silica cartridge eluting with heptane-EtOAc, gradient 0 to 20% EtOAc. Amount obtained: 0.9 g, 3.7 mmol, 37% yield. LC-MS (ESI) m/e 255 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.76 (s, 6H) 3.03 (s, 2 H) 7.14 (td, J=8.36, 1.98 Hz, 1H) 7.36 (td, J=7.96, 5.71 Hz, 1H) 7.43 (dd, J=9.57, 2.25 Hz, 1H) 7.51 (d, J=7.76 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>C(O)C>[N:15]1([C@H:12]2[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:14][CH2:13]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCCCC2)CC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Trans-4-tert-butoxycarbonylamino-aminocyclohexane (1 g) and potassium carbonate (1.3 g) were suspended in ethanol (20 mL), and then 1,5-dibromopentane (1.07 g) was added thereto. The reaction solution was stirred at 80° C. for 48 hours. After the reaction solution was cooled to room temperature, the solvent was concentrated under reduced pressure. The residue was dissolved in water (50 mL). The aqueous layer was extracted twice with dichloromethane (50 mL). The combined organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After removing the anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate: 10%-saturated aqueous ammonia-methanol=1:0→10:1) to obtain the title compound (492 mg) having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:19][CH:20]=2)[S:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)(=[O:35])=[O:34])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(C(C)(C)C)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step B of Example 1 from 3-{3-[(4-tert-butyl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester of Step A and pyridine-2sulfonyl chloride hydrochloride, of Preparation 47 using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.62 (m, 1H), 7.90 (m, 1H), 7.81 (m, 1H), 7.41 (m, 1H), 7.17 (d, 2H), 7.09 (m, 1H), 6.99 (m, 3H), 6.92 (m, 2H), 4.48 (s, 2H), 4.43 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.51 (t, 2H), 1.24 (t, 9H); MS 481 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:12]([C:18](OCC)=[O:19])[C:13](OCC)=[O:14])[CH2:8][CH2:9][CH:10]=[CH2:11].CC(C)=O.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:7]([CH:12]([CH2:18][OH:19])[CH2:13][OH:14])[CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCC(C(=O)OCC)C(=O)OCC
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C=CCCCC(CO)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A solution of 13.8 g of lithium aluminium hydride in 500 ml of tetrahydrofuran was treated dropwise under nitrogen at 0°-5° C. within 1 hour with a solution of 33.2 g of diethyl (4-pentenyl)malonate in 125 ml of tetrahydrofuran. The mixture was stirred overnight at room temperature and then heated to boiling for 3 hours. After cooling there were cautiously added dropwise to the reaction mixture firstly 25 ml of acetone and then 25 ml of saturated sodium hydrogen carbonate solution. The resulting slurry was suction filtered and the residue on the suction filter was washed four times with tetrahydrofuran. Concentration of the filtrate gave 17.8 g of 2-(4-pentenyl)-1,3-propanediol (purity 89%) as a yellow liquid.
Reaction SMILES: [Mg].[CH3:2][O:3][Si:4](OC)([O:7][CH3:8])[O:5][CH3:6].Br[C:12]1[CH:25]=[CH:24][C:23]2[S:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:15][C:14]=2[CH:13]=1>C1COCC1>[CH3:2][O:3][Si:4]([O:7][CH3:8])([O:5][CH3:6])[C:12]1[CH:25]=[CH:24][C:23]2[S:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:15][C:14]=2[CH:13]=1
Reactant: CO[Si](OC)(OC)OC
Reactant: Brc1ccc2c(c1)Sc1ccccc1S2
Agent: [Mg]
Solvent: C1CCOC1
Product: CO[Si](OC)(OC)c1ccc2c(c1)Sc1ccccc1S2
Reaction time: 0.17 h
Yield: 60 %

Procedure:
A 3-neck 1 L flask was filled with magnesium turnings (5 g), THF (200 g) and tetramethoxysilane (50 g), and heated to reflux. 2-Bromothianthrene (40 g), prepared analogously to Example 3A was added to the flask in 10 g portions. Grignard started within 10 minutes. The reaction was allowed to cool for 1 hour, after which magnesium salts were precipitated with hexanes (200 mL). GC/MS of the solution showed that along with some thianthrene, 2-(trimethoxysilyl)thianthrene was obtained in ˜60% yield (FIG. 7).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[CH:3]=1.Br[CH:13]([CH:16]=O)[CH:14]=[O:15].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[S:10][C:13]([CH:14]=[O:15])=[CH:16][N:11]=2)[CH:3]=1
Reactant: O=CC(Br)C=O
Reactant: Cc1ccnc(NC(N)=S)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccnc(Nc2ncc(C=O)s2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
A mixture of (4-methylpyridin-2-yl)-thiourea (334 mg, 2 mmol), 2-bromomalonaldehyde (302 mg, 2 mmol) and sodium acetate (250 mg, 3.0 mmol) in acetic acid (5 mL) was stirred at 100° C. for 3 h. The mixture was cooled to RT and diluted with water and the precipitate formed was collected, washed with water and dried to afford 2-(4-methylpyridin-2-ylamino)-thiazole-5-carbaldehyde (350 mg, 80%). MS m/z 220 (M+H)+.
Reaction SMILES: CC(=CC)C.OP([O-])(O)=O.[Na+].Cl([O-])(=O)(=O)=[O:13].[Na+].[CH:18]1([CH2:21][O:22][C:23]2[CH:24]=[C:25]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([CH2:38][CH:39]=[O:40])[CH:36]=4)[N:31]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[CH:43]=4)[C:30]=3[C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH:26]=[CH:27][CH:28]=2)[CH2:20][CH2:19]1>C(O)(C)(C)C.O.C(OCC)(=O)C>[CH:18]1([CH2:21][O:22][C:23]2[CH:24]=[C:25]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([CH2:38][C:39]([OH:13])=[O:40])[CH:36]=4)[N:31]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[CH:43]=4)[C:30]=3[C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH:26]=[CH:27][CH:28]=2)[CH2:20][CH2:19]1
Reactant: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(CC=O)ccc2n1Cc1cccc(OC)c1
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(CC(=O)O)ccc2n1Cc1cccc(OC)c1
Reaction time: 24 h
Yield: 20 %

Procedure:
2-Methyl-2-butene (2 mL), sodium phosphate monobasic (307 mg, 2.6 mmol) and sodium perchlorate (307 mg, 3.4 mmol) were added to a stirred solution of ethyl 3-[3-(cyclopropylmethoxy)phenyl]-1-(3-methoxybenzyl)-5-(2-oxoethyl)-1H-indole-2-carboxylate (Example 138, 169 mg, 0.34 mmol) in tert-butanol (8 mL) and water (3 mL). The reaction was stirred for 24 h and then diluted with ethyl acetate (100 mL). The solution was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Flash chromatography of the residue over silica gel using 60% ethyl acetate/hexane afforded 35 mg (20%) of the product. The product had: 1H NMR (300 MHz, acetone-D6) δ 6.96-7.57 (m, 8 H), 6.58-6.80 (m, 3 H), 5.83 (s, 2 H), 4.11 (q, 2 H), 3.90 (d, 2 H), 3.70 (s, 3 H), 3.67 (s, 2 H), 1.24-1.40 (m, 1 H), 1.03 (t, 3 H), 0.55-0.65 (m, 2 H), 0.35-0.46 (m, 2 H); mass spectroscopy gave M−H+=512.5 (calc'd exact mass for C31H31NO6=513.22).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH3:34])[CH:4]([NH:11][C:12]1[CH:13]=[C:14]([N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C.ClCCl>[ClH:1].[CH3:2][CH:3]([CH3:34])[CH:4]([NH:11][C:12]1[CH:13]=[C:14]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)C(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C(Nc1cc(N2CCNCC2)ccc1[N+](=O)[O-])c1ccccc1
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A saturated solution of HCl gas in anhydrous diethyl ether was added portion wise to a solution of tert-butyl 4-(3-(2-methyl-1-phenylpropylamino)-4-nitrophenyl)piperazine-1-carboxylate (145 mg, 0.32 mmol) in anhydrous dichloromethane (0.5 mL). The resulting mixture was allowed to stand at room temperature for 30 min, and conversion was monitored by LCMS. The solvent was concentrated down in vacuo and co-evaporated with diethyl ether to yield 60 mg (53%) of the title compound: 1H NMR (400 MHz, CD3OD): δ 8.04 (dd, 1H), 7.36-7.32 (m, 4H), 7.28-7.24 (m, 1H), 6.34 (br d, 1H), 5.89 (br s, 1H), 4.45 (br d, 1H), 3.50-3.20 (m, 8H), 2.18 (m, 1H), 1.09 (d, 3H), 0.98 (d, 3H). MS (ESI) m/z: Calculated: 354.26; Observed: 355.6 (M++1) [corresponding to the free base].
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6].Cl.O1CCOCC1>CO>[ClH:1].[Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Cl)c2F)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1cccc(Cl)c1F)N1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 35.1 g of tert-butyl 4-(3-chloro-2-fluorobenzoyl)piperazine-1-carboxylate and 50 ml of methanol was added a hydrochloric acid-1,4-dioxane solution (4 M, 100 ml) followed by stirring at room temperature for 2.5 hours. The reaction mixture was concentrated in vacuo and the residue was suspended in diethyl ether, filtered and collected to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:12]1([C:5]([C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[CH:3]=2)=[O:7])[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)cc1O
Yield: 45 %

Procedure:
The title compound is prepared from 3-hydroxy-4-methyl-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 45% of theory; LC (method 4): tR=1.98 min; Mass spectrum (ESI+): m/z=308 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([C:6]1[C:11]([N:12](COC)[S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:30])=[CH:8][N:7]=1)=[O:5].O>Cl.O1CCOCC1>[Br:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:24])([F:26])[F:25])[CH:17]=2)(=[O:14])=[O:15])=[CH:10][C:9]([Cl:30])=[CH:8][N:7]=1)=[O:5]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccccc1Br)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 54 %

Procedure:
A mixture of N-[2-(2-Bromo-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (100 mg, 0.167 mmol) in 3 ml of 4M HCl in dioxane and 1 mL of water was refluxed for 3 hours. After cooling to rt the mixture was concentrated, diluted with water and then sodium bicarbonate was added until pH was 6. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was further purified via flash column (30% ethyl acetate in hexane) to afford 50 mg of title compound as an off white solid. MS: (M+H)/z=555.3, (M+Na)/z=575.3.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][Se:14][C:10]=3[C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21](OC)=[O:22])=[CH:17][CH:16]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C2C=C[Se]C=2C(C2OC(C(OC)=O)=CC=2)=N1)C1C=CC=CC=1.C(N1C2C=C[Se]C=2C(C2OC(CO)=CC=2)=N1)C1C=CC=CC=1>>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][Se:14][C:10]=3[C:9]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][OH:22])=[CH:19][CH:20]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2nn(-c3ccccc3)c3cc[se]c23)cc1
Agent: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Agent: OCc1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Product: OCc1ccc(-c2nn(-c3ccccc3)c3cc[se]c23)cc1

Procedure:
Compound 66 (0.764 g, 0.002 mole) was used to replace compound 55 in the preparation of compound 57 to afford compound 68. Yield: 0.585 g (82.9%); white needle crystals; mp 133-134° C.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:21])[C:4]2[C:9]([O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:8]1[NH:18][N:19]=[CH:20][C:7]1=[CH:6][CH:5]=2.[Cl:22][O-].[Na+]>CCO>[Cl:22][C:20]1[C:7]2=[CH:6][CH:5]=[C:4]3[C:9]([O:10][C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([I:1])[C:3]3=[O:21])=[C:8]2[NH:18][N:19]=1
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccc1cn[nH]c12
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1c(I)c(-c2ccccc2)oc2c1ccc1c(Cl)n[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a stirred solution of 7-iodo-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one (73 mg, 0.188 mmol) in EtOH (10 mL), with cooling in a 10° C. water bath, was added sodium hypochlorite (10% aqueous solution, 9 mL). After 15 minutes, the temperature was allowed to increase to RT. After a further 30 minutes, the reaction mixture was concentrated in vacuo and the remaining reside was partitioned between EtOAc and water. The resulting biphasic mixture was separated, the aqueous phase was further extracted with EtOAc, the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and evaporated in vacuo to afford the title compound (44 mg, 55%) as a cream solid. LCMS (Method H): RT=3.75 min, [M+H]+=423/425.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH3:16])[NH:8]2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCCCC=Cc1cc2ccc(Cl)cc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCc1cc2ccc(Cl)cc2[nH]1
Reaction time: 5 h

Procedure:
6-Chloro-2-hex-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred for 5 hours. Then the reaction mixture was filtered through Celite. The solvent was evaporated to give 6-Chloro-2-hexyl-1H-indole.