Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[N:18][C:17]([C:21](OCC)=[O:22])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH2:1]([N:8]1[C:20]2[CH:19]=[N:18][C:17]([CH2:21][OH:22])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2c3ccccc3n(Cc3ccccc3)c2cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
Compound 33 (3.3 g, 10 mmol) was mixed with anhydrous THF (100 ml). The mixture was added dropwise to a mixed solution of LiAlH4 (1.2 g, 30 mmol) and anhydrous THF (100 ml). After that, the mixture was refluxed for 10 h. Then the mixture was cooled to room temperature. 10% NaOH (50 ml) was added into the mixture and then stirred for 20 minutes. The mixture was extracted with ethyl acetate, the organic phases were combined and washed with water and brine, dried over anhydrous sodium sulfate, filtered, evaporated and purified by silica gel column chromatography with ethyl acetate as the eluent. Upon recrystallization, white solids (1.5 g, 52%) were obtained, mp 120-122° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]([F:10])([F:9])[F:8])[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])O.[Na+].[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](ON3C(=O)CCC3=O)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl>O.O1CCCC1>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:1][CH:2]([C:7]([F:10])([F:9])[F:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NC(CC(=O)O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 47.5 %

Procedure:
3-Amino-4,4,4-trifluorobutyric acid (10 g, 63.7 mmol) was added to a solution of sodium hydrogen carbonate (6.95 g, 82.8 mmol) in water (100 mL). A solution of 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy-2,5-pyrrolidinedione (Fmoc-OSu; 25.78 g, 76.4 mmol) in tetrahydrofuran (200 mL) was added. The solution was stirred at room temperature for 19 h and then acidified to pH 1 with 3 M HCl (250 mL). The mixture was extracted with ethyl acetate (250 mL then 100 mL) and the combined organic layers were washed with saturated brine (3×100 mL), dried (Na2SO4), filtered and concentrated to approximately 200 mL. Crystallization occurred on concentration. The mixture was allowed to stand for 10 min, then the solid was filtered off, washed with ethyl acetate and dried in a vacuum oven at 50° C. to give 3-[N-[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4,4,4-trifluorobutyric acid (11.47 g) as a white solid, mp 187-189° C. The mother liquor was concentrated to 80 mL. Crystallization occurred on concentration. The solid was filtered off, washed with ethyl acetate and dried in a vacuum oven at 50° C. to give a second batch of product (4.69 g). The overall yield was16.16 g (67%).
Reaction SMILES: [H-].[Na+].[Si]([O:20][CH2:21][CH2:22][OH:23])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[CH:32][N:33]=2)[N:30]=1>CN(C)C=O>[OH:23][CH2:22][CH2:21][O:20][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[CH:32][N:33]=2)[N:30]=1
Reactant: CC(C)(C)[Si](OCCO)(c1ccccc1)c1ccccc1
Reactant: Clc1ccc2ncnn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCOc1ccc2ncnn2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
60% Oily sodium hydride (510 mg) was suspended in N,N-dimethylformamide (70 ml), followed by addition of 2-(t-butyldiphenysilyoxy)ethanol (3.83 g). The mixture was stirred at room temperature for 1 hour, followed by addition of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine (1.98 g). The mixture was stirred at room temperature for 5 hours and poured into ice-water, followed by extraction with ethylether. The extract was washed with an aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 ml), followed by addition of tetra-n-butylammoniumfluoride trihydrate (2.02 g). The mixture was stirred at room temperature for 10 minutes and concentrated under reduced pressure. The residue was subjected to silica-gel column chromatography and eluted with a mixture of ethyl acetate and hexane (1:1). Fractions containing the objective compound were collected and concentrated to yield the title compound (0.875 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[C:29](I)[C:24]=4[O:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11].[CH3:32]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+].CO>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[C:29]([CH3:32])[C:24]=4[O:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: Nc1ncc(I)c2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc(N)c2c(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)coc12
Temperature: 100 °C
Reaction time: 15 h
Yield: 13.9 %

Procedure:
A mixture of 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-iodofuro[3,2-c]pyridin-4-amine (253 mg, 0.476 mmol), trimethylboroxine (0.07 mL, 0.502 mmol), PdCl2(dppf)-CH2Cl2 adduct (19 mg, 0.023 mmol), and K2CO3 (197 mg, 1.425 mmol) in 1,4-Dioxane (2.5 mL) and Water (0.5 mL) was degassed with Nitrogen for 10 minutes. The vial was then capped and the mixture was stirred at 100° C. for 15 hr. LCMS showed a mixture of starting material (20%), desired product (36%), and the deiodo byproduct (40%). The mixture was filtered, rinsing with EtOAc (about 35 mL). The filtrate was washed with water (1×25 mL) and brine (1×25 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The recovery was fairly low (<200 mg), so the aqueous phases were combined and extracted with methylene chloride (3×25 mL), and the extracts were dried (Na2SO4), filtered, combined with the EtOAc layer from the previous work-up, and concentrated in vacuo (total mass>200 mg). The residue was purified by reverse phase HPLC (Gilson, C18, 25% to 45% CH3CN in water with 0.1% TFA, 8 minute gradient). The product fractions were concentrated, taken up in MeOH, and passed through a PL-HCO3 cartridge. The filtrate was concentrated in vacuo, triturated with ether, and dried in the vacuum oven overnight. NMR indicated that the compound was still a TFA salt, and it showed an impurity The solid was taken up in DCM (5 mL) and poured into saturated aqueous NaHCO3 (5 mL). The organic layer was collected and the aqueous layer was extracted with methylene chloride (2×5 mL). The organic phases were combined, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was repurified by flash chromatography (Analogix, 12 g SiO2, 50%-100% EtOAc in hexanes gradient over 7.5 minutes, EtOAc for 2.5 minutes, then 0-5% MeOH in EtOAc gradient over 10 minutes) to give 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methylfuro[3,2-c]pyridin-4-amine (29 mg, 0.066 mmol, 13.79% yield) as a white solid. LC/MS (ES) m/z=420 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.30 (s, 3H), 3.28 (t, J=8.21 Hz, 2H), 3.96 (s, 2H), 4.30 (t, J=8.46 Hz, 2H), 5.31 (s, 2H), 7.14-7.34 (m, 4H), 7.41 (s, 1H), 7.69 (s, 1H), 7.95 (s, 1H), 8.12 (d, J=8.34 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:34][N:35](C=O)[CH3:36].CNC.O>CCOC(C)=O>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:11]1[C:12]2[CH:17]=[N:16][N:15]([CH:18]([CH3:19])[CH3:20])[C:13]=2[N:14]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:35]([CH3:36])[CH3:34])[CH:4]=2)[CH:10]=1)=[O:22]
Reactant: CN(C)C=O
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CBr)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: CNC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CN(C)C)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 40 %

Procedure:
To a stirred solution of 6-(3-(bromomethyl)phenyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in a DMF, dimethylamine (5 equiv.) was added at 0° C. & resulting reaction mixture stirred for overnight. After completion of reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude material which was purified by column chromatography to give pure final compounds (40% yield). LCMS: 473.20 (M+1)+; HPLC: 99.89% (@ 254 nm) (Rt; 5.325); 1H NMR (DMSO-d6, 400 MHz) δ 11.52 (s, 1H), 8.96 (bs, 1H), 8.35 (s, 1H), 8.13-8.10 (m, 3H), 7.50 (t, J=8.4 Hz, 1H), 7.43-7.41 (m, 1H), 5.89 (s, 1H), 5.34-5.31 (m, 1H), 4.41 (d, J=4 Hz, 2H), 3.50 (s, 2H), 2.23 (s, 3H), 2.19 (s, 6H), 2.12 (s, 3H), 1.54 (d, J=6.8 Hz, 6H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:35])[C@:7]1([OH:34])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([F:31])([C@@H:22]([O:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:32])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@@H:8]1[CH3:33])(=[O:3])[CH3:2].[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37].COC(C)(C)C.CCCCCC.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:36]([NH:38][C:39](=[O:40])[O:34][C@:7]1([C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([F:31])([C@@H:22]([O:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:32])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@@H:8]1[CH3:33])[C:6](=[O:35])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH3:37]
Reactant: CCN=C=O
Reactant: CC(=O)OCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C
Solvent: ClC(Cl)Cl
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: CCNC(=O)O[C@]1(C(=O)COC(C)=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C
Temperature: 25 °C
Yield: 62.5 %

Procedure:
To a mixture of (11β,16β)-9-fluoro-17-hydroxy-16-methyl-3,20-dioxo-11-[(trimethyl-silyl)oxy]-pregna-1,4-dien-21-yl acetate (3.11 g, 6.15 mmol) in 41 mL of toluene was added neat ethyl isocyanate (20.5 mL, 259 mmol) and the mixture was refluxed for 48 hours. The resulting solution was cooled to room temperature and evaporated under vacuum to leave a slightly gummy solid. Flash chromatography through a 1 kg column of silica gel eluting with t-butyl methyl ether/hexane/chloroform (1:1:1) gave 2.22 g of the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C@H:10]1[O:39][C@H:38]([CH2:40][O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:11]1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:49]([O:51][C:52](=[O:58])[C:53](=[N:56][OH:57])[CH2:54]Br)[CH3:50].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:49]([O:51][C:52](=[O:58])[C:53](=[N:56][OH:57])[CH2:54][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C@H:10]1[O:39][C@H:38]([CH2:40][O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:29]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:11]1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:50]
Reactant: c1ccc(COC[C@H]2O[C@H](c3cc4ccccc4[nH]3)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reactant: CCOC(=O)C(CBr)=NO
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(Cc1c([C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[nH]c2ccccc12)=NO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.3 %

Procedure:
First, 2.08 g (3.24 mmol) of (1R)-1,5-anhydro-1-C-(2-indolyl)-2,3,4,6-tetra-O-benzyl-D-mannitol [compound (VII) wherein R1 to R4 are benzyl] was dissolved in dichloromethane (160 ml). Then, 1.36 g (6.49 mmol) of 3-bromo-2-hydroxyiminopropionic acid ethyl ester [compound (VIII) wherein R6 is ethyl] and 1.03 g (9.74 mmol) of sodium carbonate powder were added to the mixture and stirred at room temperature for about 1.5 hours. Then, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture which was then subjected to extraction with dichloromethane. The extracted solution was washed with water and then dried on anhydrous sodium sulfate. After removal of the solvent by distillation, the residue was fractionated by column chromatography on silica gel [silica gel: Merck Kieselgel 60 (230-400 mesh ASTM); elution solvent: n-hexane and ethyl acetate (3:1)] to give 1.04 g (recovery 50%) of the starting material and 0.93 g (yield 37%) of 2-hydroxyimino-3-[2-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)indole-3-yl]propionic acid ethyl ester [compound (IX) wherein R1 to R4 are benzyl and R6 is ethyl].
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.[CH3:12]O>>[NH2:1][C:2]1([C:8]([O:10][CH3:12])=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CO
Reactant: NC1(C(=O)O)CCOCC1
Agent: Cl
Product: COC(=O)C1(N)CCOCC1

Procedure:
A solution 4-aminotetrahydro-2H-pyran-4-carboxylic acid (0.50 g, 3.4 mmol) in MeOH (10 mL) was saturated with HCl gas at 0-5° C., and the mixture was then heated at reflux for 3.5 h. The solvents were evaporated in vacuo, the residue was dissolved in saturated aqueous NaHCO3 and the aqueous solution was extracted with CH2Cl2 (2×50 mL). The combined extracts were dried (MgSO4) and evaporated in vacuo to give methyl 4-aminotetrahydro-2H-pyran-4-carboxylate (410 mg, 2.58 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:16]([NH:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(F)c1
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccnc(F)c1
Temperature: 25 °C
Reaction time: 30 h
Yield: 48.9 %

Procedure:
112 mg (1 mmol) of 2-fluoro-4-aminopyridine was added to 9 ml of dry benzene and to the resulting solution was further added 119 mg (1 mmol) of phenyl isocyanate. After stirring at room temperature for 30 hrs., the crystals which deposited were collected by filtration and then subjected to chromatography in a conventional manner using alumina. After developing the column with a benzene-ethyl acetate (3:1 by volume) solvent mixture, eluate containing the objective compound was collected. After distilling solvent off under reduced pressure, the residue was recrystallized from an ethyl acetate-n-hexane solvent mixture to give 113 mg of the objective compound: yield 48.9%; m.p. 179°-180° C.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1)=[CH2:2].C([O-])([O-])=O.[K+].[K+].N[C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:17]2[CH:18]=[CH:19][C:20]([S:23]([N:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[N:7][CH:8]=1)=[CH2:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Reactant: C=Cc1cnc(N)cn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C=Cc1cnc(Nc2ccc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cn1
Temperature: 100 °C
Yield: 65.2 %

Procedure:
To a solution of 5-vinylpyrazin-2-amine (150 mg, 1.24 mmol) in 2-buOH (4 mL) were added K2CO3 (512 mg, 3.71 mmol), and tert-butyl 4-(4-aminophenylsulfonyl)piperazine-1-carboxylate (421 mg, 1.24 mmol). The reaction mixture was degassed for 10 minutes. To a mixture were added Pd2(dba)3 (76 mg, 0.07 mmol) and X-phos (53 mg, 0.11 mmol). The reaction mixture was heated to 100° C. for 6 hours after which, it was filtered with a pad of celite and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (20% to 30% Ethyl acetate/Hexane) as a solvent to afford title compound (360 mg, 65% yield). MS m/z: 446 [M+1].
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][S:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)(=[O:10])=[O:9]>CO.[Pd]>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][S:8]([NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][OH:1])(=[O:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)NCCOCCO
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1CS(=O)(=O)NCCOCCO
Reaction time: 8 h

Procedure:
To a stirred solution of N-[2-(2-hydroxyethoxy)ethyl]-1-(2-nitrophenyl)-methanesulfonamide (0.145 g, 0.48 mmol) in methanol (10 ml) under an atmosphere of nitrogen was added 10% Pd/C (10 Wt %, 15 mg) in one portion. The reaction was evacuated, placed under an atmosphere of hydrogen (1 bar) and stirred vigorously overnight. The reaction was filtered through celite and the filtrate was concentrated in vacuo to afford 1-(2-aminophenyl)-N-[2-(2-hydroxyethoxy)ethyl]methanesulfonamide as product (0.105 g, 81%); LCMS Rt=2.06 min, m/z (APCI) 297 (M+Na).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:7]=[C:8]([C:17]2[NH:18][C:19](=[O:37])[C:20]3[C:21](=[C:23]([CH2:35][CH3:36])[N:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]4)[N:25]=3)[N:22]=2)[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][CH:11]=1)(=[O:5])[CH3:4]>CO>[C:32]([N:29]1[CH2:28][CH2:27][CH:26]([N:24]2[C:23]([CH2:35][CH3:36])=[C:21]3[N:22]=[C:17]([C:8]4[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][CH:11]=[C:6]([CH:3]([OH:5])[CH3:4])[CH:7]=4)[NH:18][C:19](=[O:37])[C:20]3=[N:25]2)[CH2:31][CH2:30]1)(=[O:34])[CH3:33]
Reactant: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CCN(C(C)=O)CC3)nc2c(=O)[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCOc1ncc(C(C)O)cc1-c1nc2c(CC)n(C3CCN(C(C)=O)CC3)nc2c(=O)[nH]1
Yield: 83.3 %

Procedure:
Sodium borohydride (6 mg, 0.15 mmol) was added to a suspension of the title compound from example 131 (140 mg, 0.3 mmol) in dry methanol (3 ml) at 0° C. under nitrogen. After 30 min the solvent was removed in vacuo, and the residue partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated, and the aqueous layer was extracted further with ethyl acetate (2×20 ml). Combined organic layers were washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (98:2 to 95:5 methylene chloride:methanol as eluent) to yield the title compound as a white foam (120 mg, 0.25 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1.C(N(CC)CC)C.[O:24](C(OC(C)(C)C)=O)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:25](=[O:24])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1
Reactant: NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
To a mixture of Example 260a (2.60 g, 7.39 mmol) and triethylamine (1.340 mL, 9.61 mmol) in tetrahydrofuran (50 mL) was added BOC2O (1.78 g, 8.13 mmol) at 0° C. The ice bath was removed and the reaction was stirred at room temperature for 90 minutes. The reaction was diluted with EtOAc and washed with brine and sat. NaHCO3. The organic layer was dried over MgSO4, filtered, concentrated, and purified on an 80 g column using the ISCO Companion flash system eluting with hexane/EtOAc (8:2 to 6:4) to give 1.78 g of the title compound.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([CH2:21]O)[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[NH:28]1CCO[CH2:30][CH2:29]1.C(S(C1C=C(C2C=C(CN(C)C)C=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([CH2:21][NH:28][CH2:29][CH3:30])[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: C1COCCN1
Reactant: CCS(=O)(=O)c1cccc(-c2cc(CO)cc3[nH]c4ncc(C)cc4c23)c1
Agent: CCS(=O)(=O)c1cccc(-c2cc(CN(C)C)cc3[nH]c4ncc(C)cc4c23)c1
Product: CCNCc1cc(-c2cccc(S(=O)(=O)CC)c2)c2c(c1)[nH]c1ncc(C)cc12

Procedure:
The title compound was prepared from Compound 133 and morpholine according to the procedure outline for the preparation of Compound 134. 1H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 8.13 (s, 1H), 8.04 (d, 1H, J=7.6 Hz), 7.97 (d, 1H, J=7.6 Hz), 7.84 (t, 1H, J=7.6 Hz), 7.64 (s, 1H), 7.54 (s, 1H), 7.22 (s, 1H), 4.25 (s, 2H), 3.34 (q, 2H, J=7.2 Hz), 2.99-3.07 (m, 2H), 2.25 (s, 3H), 1.20-1.29 (m, 6H). MS (ES) [m+H] calc'd for C23H25N3O2S, 408; found 408.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH2:13].[C:14]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:15][CH:16]=1)=[O:21]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(F)cc12)c1ccc(-c2ccccc2)cc1
Yield: 75.6 %

Procedure:
N-(2-(5-Fluoro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtained following Method C starting from 2-(5-fluoro-1H-indol-3-yl)ethanamine (0.100 g, 0.561 mmol), biphenyl-4-carbonyl chloride (0.130 g; 0.589 mmol), and triethylamine (0.095 mL; 0.673 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.152 g (76%) of N-(2-(5-Fluoro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.