Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:31])[N:5]([C:28](=[O:30])[CH3:29])[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1.[I-].[Na+].[Cs].[C:35]([N:42]1[CH2:50][CH2:49][CH:45]([C:46]([OH:48])=[O:47])[CH2:44][CH2:43]1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C(#N)C>[C:38]([O:37][C:35]([N:42]1[CH2:50][CH2:49][CH:45]([C:46]([O:48][CH2:2][O:3][C:4](=[O:31])[N:5]([C:28](=[O:30])[CH3:29])[CH2:6][C@@H:7]2[O:11][C:10](=[O:12])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]4)=[C:15]([F:27])[CH:14]=3)[CH2:8]2)=[O:47])[CH2:44][CH2:43]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCCl
Agent: [Cs]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 72 %

Procedure:
To (R)-acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid chloromethyl ester (10) (751.8 mg, 1.58 mmol) and sodium iodide (236.0 mg, 1.58 mmol) in acetonitrile (30 mL), is added the cesium salt of N-BOC-isonipecotic acid (884.2 mg, 2.45 mmol). The mixture is heated to reflux overnight. After cooling to RT, the mixture is filtered and washed with dichloromethane. The filtrate is diluted with CH2Cl2 and water and the layers are separated. The aq layer is extracted with dichloromethane twice and the combined organic layers are washed with water, brine, dried over sodium sulfate and conc in vacuo. Purification by silica gel chromatography gave the title compound in 72% yield (757.3 mg, 1.13 mmol). 1H NMR (400 MHz, CDCl3): δ 7.47 (dd, 1H), 7.24 (t, 1H), 7.14 (dd, 1H), 5.88 (s, 2H), 4.78-4.85 (m, 1H), 4.18 (dd, 1H), 4.08 (t, 2H), 4.03 (dd, 2H), 3.67 (dd, 1H), 3.13-3.20 (m, 4H), 3.10 (dt, 1H), 2.83 (t, 2H), 2.60 (tt, 1H), 2.59 (s, 3H), 2.35-2.46 (m, 2H), 2.17-2.23 (m, 2H), 1.90-1.96 (m, 2H), 1.57-1.686 (m, 2H) 1.45 (s, 9H). MS-APCI (m/z+): 570.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1>CO.[Ni]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Cl:1])[C:3]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:4]3[N:10]=2)=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3c(Nc4ccccc4)c(Cl)cnc3[nH]2)cc1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(-c2nc3c(Nc4ccccc4)c(Cl)cnc3[nH]2)cc1
Reaction time: 0.75 h
Yield: 86.4 %

Procedure:
6-Chloro-2-(4-nitrophenyl)-N-phenyl-3H-imidazo[4,5-b]pyridin-7-amine (0.35 g, 1.0 mmol) was dissolved in 50 ml methanol. A catalytic amount of Raney-Nickel was added. The solution was shaken for 45 min under hydrogen pressure (3 atm). The catalyst was filtered off and the solvent removed in vacuo. The crude product was purified by column chromatography on silica, eluting with EtOAc/MeOH 9:1, giving the title product (0.29 g, 85%).
Reaction SMILES: CO.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][C:13]3[C:17]([OH:30])([C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)[O:16][C:15](=[O:31])[C:14]=3[C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[CH:11][C:6]=2[O:5][CH2:4]1>O>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12]/[C:13](/[C:17](=[O:30])[C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)=[C:14](/[C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)\[C:15]([OH:31])=[O:16])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: COc1ccc(C2=C(Cc3ccc4c(c3)OCO4)C(O)(c3cc(OC)c(OC)c(OC)c3)OC2=O)cc1
Solvent: O
Solvent: CO
Product: COc1ccc(/C(C(=O)O)=C(/Cc2ccc3c(c2)OCO3)C(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Reaction time: 16 h

Procedure:
To 250 mL methanol was added 4-benzo[1,3]dioxol-5-ylmethyl-5-hydroxy-3-(4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-5H-furan-2-one 4.0 g (7.89 mmol), giving solution. To the solution was added 250 mL water containing 15.8 mL 1.001N NaOH. The solution was irradiated with a Hanovia ultraviolet light contained in a quartz reactor (Ace Glass, Catalog 1200, #7840-180) for 16 hours at ambient temperature. The solution was evaporated in vacuo to remove the methanol. The residual aqueous solution was extracted repeatedly with ethyl ether, while the pH of the aqueous phase was adjusted incrementally between 7.5 and 8 by addition of 3N HCl. The aqueous phase was then acidified to pH 1 with HCl and extracted with ethyl ether. The ether extract was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the ether solution under reduced pressure gave a foam, 1.44 g. The residue was purified by chromatography on 50 g silica gel eluted with 1% methanol in chloroform. The appropriate fractions were evaporated to a solid, 0.77 g. The product was identified by 1H NMR, MS [M-H]+ =505.4 Da. and microanalysis.
Reaction SMILES: [CH2:1]([N:8]1[C:19](=[O:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(O)C(N)(CO)CO>ClC(Cl)C>[CH2:1]([N:8]1[C:19](=[O:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][C:10]2([CH2:11][CH2:12][N:13]([C:31]([NH:30][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:32])[CH2:14][CH2:15]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCC1
Reactant: O=C1c2ccccc2OC2(CCNCC2)CN1Cc1ccccc1
Agent: NC(CO)(CO)CO
Solvent: CC(Cl)Cl
Product: O=C(NC1CCCC1)N1CCC2(CC1)CN(Cc1ccccc1)C(=O)c1ccccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound prepared in Example 30 (0.010 mmol) in dichloroethane (0.7 mL) was added cyclopentylisocyanate (0.020 mmol), the mixture was stirred overnight at 25° C. To the reaction mixture was added PS-trisamine (Argonaut, product number 800229, loading; 4.36 mmol/g) (6.9 mg). After stirring overnight at 25° C., the mixture was filtered and the filtrate was concentrated to give the compound of the present invention having the following physical data.
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7].NC1C=C2C(=CC=1)C(=O)OC2.C1(C2(CC(=O)C(O)=O)CC2)C=CC=CC=1>>[C:18]1([C:16]2([CH2:15][C:14](=[O:25])[C:13]([NH:12][C:11]3[CH:2]=[C:3]4[C:8](=[CH:9][CH:10]=3)[C:6](=[O:7])[O:5][CH2:4]4)=[O:26])[CH2:24][CH2:17]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Agent: Nc1ccc2c(c1)COC2=O
Agent: O=C(O)C(=O)CC1(c2ccccc2)CC1
Product: O=C(CC1(c2ccccc2)CC1)C(=O)Nc1ccc2c(c1)COC2=O

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 3-(1-phenyl-cyclopropyl)-2-oxo-propionic acid, melting point 132-138° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33])[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2)[CH3:2].Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:39][CH:38]=1)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2)[CH3:2]
Reactant: ClCc1ccc(CCc2ccccc2)cc1
Reactant: CCOC(=O)CCCCN(CCc1ccccc1O)C1CCCc2nc(C(=O)OCC)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCN(CCc1ccccc1OCc1ccc(CCc2ccccc2)cc1)C1CCCc2nc(C(=O)OCC)ccc21
Reaction time: 6 h

Procedure:
Under argon, 500 mg (1.07 mmol) of ethyl 5-{(5-ethoxy-5-oxopentyl)[2-(2-hydroxyphenyl)-ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate, 246 mg (1.07 mmol) of 1-(chloromethyl)-4-(2-phenylethyl)benzene and 295 mg (2.13 mmol) of potassium carbonate in 5 ml of DMF were heated to 80° C. and stirred at this temperature for 6 hours. After cooling, water and ethyl acetate were added to the reaction mixture and the phases were then separated. The organic phase was washed twice with water and once with saturated sodium chloride solution and then concentrated to dryness. This gave 760 mg (1.01 mmol, content 88%, 94% of theory) of the target compound.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH2:42][CH2:43]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:43][CH2:42][C:27]2[N:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[S:38][CH:39]=[CH:40][CH:41]=4)=[CH:33][CH:32]=3)[O:30][C:26]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3cccs3)cc2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)c(F)c2)C(=O)O)cc1

Procedure:
A mixture of 2-(3,4-difluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol) (see Ex. 45, Part C), toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)-ethyl ester (0.030 mmol) (see Ex. 3, Part B) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-(3,4-difluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, 2H, J=8.8 Hz), 7.98 (bs, 1H), 7.67 (d, 2H, J=8.8 Hz), 7.42 (dd, 1H, J=4.0, 1.0 Hz), 7.36 (d, 1H, J=4.8 Hz), 7.17 (d, 2H, J=8.8 Hz), 7.12 (dd, 1H, J=4.8, 4.0 Hz), 7.00 (q, 1H, J=9.2 Hz), 6.83 (d, 2H, J=8.8 Hz), 6.76 (ddd, 1H, J=11.6, 6.8, 3.2 Hz), 6.63–6.59 (m, 1H), 4.21 (t, 2H, J=6.6 Hz), 3.23 and 3.10 (d of ABq, 2H, J=14.2 Hz), 3.07 (t, 2H, J=6.6 Hz), 2.43 (s, 3H), 1.38 (s, 3H).
Reaction SMILES: [OH-].[Li+].[CH:3]1([O:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2/[CH:17]=[CH:18]/[C:19]2[N:23]([C:24]3[N:29]=[N:28][C:27]([C:30]([O:32]CC)=[O:31])=[CH:26][CH:25]=3)[C:22]3[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=3[N:20]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>C(O)C>[CH:3]1([O:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2/[CH:17]=[CH:18]/[C:19]2[N:23]([C:24]3[N:29]=[N:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)[C:22]3[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=3[N:20]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)c1ccc(-n2c(/C=C/c3cccc(OC)c3OC3CCCC3)nc3ccccc32)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3ccccc3n2-c2ccc(C(=O)O)nn2)c1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.4 %

Procedure:
This compound was prepared by adding aqueous solution of lithium hydroxide (35 mg, 0.826 mmol) to a stirred solution of Example 19 that is Ethyl 6-{2-[(E)-2-(2-[Cyclopentyloxy]-3-methoxyphenyl)vinyl]-1H-benzimidazol-1-yl}pyridazine-3-carboxylate (200 mg, 0.413 mmol) in ethanol (5 ml) and stirring the reaction mixture at room temperature for 2 h. After completion of reaction the reaction mixture was acidified with 10% HCl until pH 4 was reached and at this pH the product precipitated out as a yellow solid which was filtered, washed with diethylether and dried under vaccum to get 210 mg of off-white solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[NH2:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].CC1C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>>[C:10]([CH2:9][NH:8][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: NCC(=O)OCc1ccccc1
Reactant: C=CC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNCC(=O)OCc1ccccc1
Yield: 73 %

Procedure:
Ethyl acrylate (24.4 mL, 225 mmol) and glycine, benzyl ester, p-toluenesulfonate (50.0 g, 148 mmol) were combined in a 250 mL round bottom flask. With stirring, triethylamine (24.8 mL, 178 mmol) was added via syringe and the reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was partitioned between ethyl acetate (660 mL) and 10% aqueous Na2CO3 (300 mL). The organics were washed with water (100 mL) and saturated NaCl (100 mL). The organics were dried over MgSO4, filtered and concentrated in vacuo followed by pumping under high vacuum to yield N-(carbobenzyloxymethyl)-3-aminopropionic acid, ethyl ester (39.3 g, 73% yield) as a yellow oil.
Reaction SMILES: CCN[C:4]([C@H:6]1[O:10][C@@H:9]([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=[O:5].C1([C@@]2(N3C4N=CN=C(N)C=4N=C3)O[C@H](CO)[C@@H](O)[C@H]2O)CCCCC1.[Mg+2].[Cl-].[Cl-]>C1(C(NC2N=C(N)C3N=CN(C=3N=2)[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)(C)C)C=CC=CC=1>[C@@H:9]1([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[O:10][C@H:6]([CH2:4][OH:5])[C@@H:7]([OH:22])[C@H:8]1[OH:21]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: CC(C)(Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Agent: Nc1ncnc2c1ncn2[C@]1(C2CCCCC2)O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Cl-]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 1 h

Procedure:
Incubation tubes, in triplicate, receive 100 μl of [3H]NECA (94 nM in the assay), 100 μl of 1 μM cyclohexyladenosine (CHA), 100 μl of 100 mM MgCl2, 100 μl of 1 IU/ml adenosine deaminase, 100 μl of test compounds at various concentrations over the range of 10-10M to 10-4M diluted with assay buffer (50 mM Tris-HCl, pH 7.7) and 0.2 μl of membrane suspension (5 mg wet weight), in a final volume of 1 ml of 50 mM Tris-HCl, pH 7.7. Incubations are carried out at 25° C. for 60 minutes. Each tube is filtered through GF/B glass fiber filters using a vacuum. The filters are rinsed two times with 5 ml of the ice-cold buffer. The membranes on the filters are transferred to scintillation vials to which 8 ml of Omnifluor with 5% Protosol is added. The filters are counted by liquid scintillation spectrometry.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=3[S:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>C1COCC1.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:18]3[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=3[S:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: Nc1ncnc2scc(-c3ccc([N+](=O)[O-])cc3)c12
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2csc3ncnc(N)c23)cc1
Yield: 97.4 %

Procedure:
A suspension of Example 58C (0.5 g, 1.83 mmol) in THF (30 mL), water (15 mL), and ethanol (40 mL) was heated to 50° C., treated with iron powder (0.616 g, 11.02 mmol), heated to between 70 and 80° C. for two hours, and filtered while hot through diatomaceous earth (Celite®). The pad was washed with TBF (10 mL) and ethanol and the combined filtrates were concentrated. The residue was partitioned between water and ethyl acetate and the aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to give 0.432 g of the desired product. MS (CI) m/e 243 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H); 7.28 (s, 1H); 7.11 (d, J=8.4 Hz, 2H); 6.68 (d, J=8.4 Hz, 2H); 5.39 (br s, 2H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH:17]([O:20][CH3:21])[O:18][CH3:19])[CH:9]=1.[NH2:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.O>CC(N(C)C)=O>[CH3:19][O:18][CH:17]([O:20][CH3:21])[C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[O:29][C:25]1[CH:24]=[C:23]([NH2:22])[CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cccc(O)c1
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 24 h

Procedure:
K2CO3 (0.17 mol) and then 4-chloro-2-dimethoxymethyl-1-nitro-benzene (0.1 mol) was added to a solution of 3-amino-phenol (0.15 mol) in DMA (200 mL) and the reaction mixture was stirred at 130° C. for 24 hours. The mixture was poured out into water and extracted with diisopropyl ether. The extract was purified by column chromatography over silica gel (eluent: CH2Cl2:CH3OH 100:0 to 65:35). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[C:18]([CH:25]([CH3:27])[CH3:26])[C:17]=1[O:28][CH2:29][CH3:30])[CH3:6].[OH-].[Na+]>CO.O1CCOCC1.Cl.O>[CH2:29]([O:28][C:17]1[C:18]([CH:25]([CH3:27])[CH3:26])=[CH:19][C:20]([CH:22]([CH3:23])[CH3:24])=[CH:21][C:16]=1[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:5]([CH3:6])=[CH:4][C:3]([OH:31])=[O:2])[CH:8]=2)[NH:12][CH:11]=1)[CH3:30]
Reactant: CCOc1c(-c2c[nH]c3ccc(C(C)=CC(=O)OC)cc23)cc(C(C)C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CCOc1c(-c2c[nH]c3ccc(C(C)=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Yield: 59.9 %

Procedure:
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-1H-indol-5-yl]-but-2-enoic acid methyl ester (77 mg, 0.14 mmol) was dissolved in methanol (1 mL)/dioxane (1 mL) and treated with 1N NaOH (1 mL) at 55° C. for 5 h. Diluted with 1N HCl (3 mL)/water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic portions were washed with brine (2×10 mL), dried (MgSO4), filtered and concentrated in vacuo to provide 68 mg. The material was purified by radial chromatography using a hexane/ethyl acetate gradient to provide 34 mg (62%) of a yellow foam. 1H NMR (250 MHz, CDCl3): δ 8.33 (bs, 1H), 8.04 (s, 1H), 7.58 (d, 1H, J=2.4), 7.44 (s, 1H), 7.29 (d, 1H, J=2.2), 7.09 (d, 1H, J=2.2), 6.27 (s, 1H), 3.56-3.38 (m, 3H), 2.95 (sep, 1H, J=6.9), 2.70 (s, 3H), 1.32 (s, 12H, J=6.9), 1.08 (t, 3H, J=7.0). MS [EI−] 404 (M−H)+.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[N:32][CH:33]=1.CC([O-])(C)C.[Na+]>>[Cl:34][C:31]1[N:32]=[CH:33][C:28]([NH:27][C:16]2[CH:15]=[C:14]([C:20]([F:23])([F:22])[F:21])[C:13]3[N:12]([CH3:24])[C@H:11]4[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]4[C:18]=3[CH:17]=2)=[CH:29][CH:30]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CN1c2c(cc(Br)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CN1c2c(cc(Nc3ccc(Cl)nc3)cc2C(F)(F)F)[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general Method A as a yellow solid (56 mg, 29%) from (4aS,9bR)-8-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45, 217 mg, 0.5 mmol), 5-amino-2-chloro-pyridine (193 mg, 1.5 mmol) and NaOt-Bu (144 mg, 1.5 mmol). MS (ESI): 383 (base, M+H).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH:11]=[O:12])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22]=1)#[N:20].C(Cl)Cl>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]>[CH:11]([C:9]1[N:10]=[C:6]2[C:5]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:4][CH:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[N:22][CH:23]=3)[N:7]2[CH:8]=1)=[O:12]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: O=Cc1cn2c(Br)cnc(N3CCOCC3)c2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(C=O)cn23)cn1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Compound 2a (156 mg, 0.500 mmol), 2-cyanopyridine-5-boronic acid pinacol ester (230 mg, 1.00 mmol), and PdCl2(dppf).DCM (40.8 mg, 0.0500 mmol), were placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with Argon gas. Dry DME (4 mL) and 2M Na2CO3 (2 mL) were added sequentially and then the reaction was stirred at 90° C. for 3 h. The reaction was cooled to rt and diluted with DCM (10 mL). The mixture was dried through a Na2SO4 pre-packed cartridge and then the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (40-g SiO2 pre-packed column, 0-100% EtOAc/DCM) to afford compound 75a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 10.08 (s, 1H), 8.93 (s, 1H), 8.17 (s, 1H), 8.02-8.10 (m, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.49 (s, 1H), 4.47 (br. s., 4H), 3.90 (t, J=4.6 Hz, 4H). LCMS calcd for C17H14N6O2: 335.1 (M+H). found: 335.1.