Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4](O)=[N:3][CH:2]=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[Si](C)(C)N[Si](C)(C)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][NH:28][C:4]2[C:5]3[C:10](=[N:9][CH:8]=[CH:7][N:6]=3)[N:1]=[CH:2][N:3]=2)=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1ncnc2nccnc12
Reactant: NCCc1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: c1ccc(COc2ccc(CCNc3ncnc4nccnc34)cc2)cc1
Temperature: 114 °C
Yield: 73.8 %

Procedure:
To a mixture of pteridin-4-ol (282 mg, 1.9 mmol) and 2-(4-benzyloxyphenyl)-ethylamine (476 mg, 2.1 mmol) and hexamethyldisilazane (5 mL) in a 25 mL round bottom flask, equipped with reflux condenser, drying tube and magnetic stir bar, was added ammonium sulfate (100 mg, 0.76 mmol). The mixture was heated to 114° C. overnight and then the solvent was removed in vacuo. The residue was suspended in H2O and filtered. The filter cake was dissolved in CH2Cl2, dried with Na2SO4, filtered, and concentrated in vacuo to provide [2-(4-benzyloxyphenyl)-ethyl]-pteridin-4-yl-amine as a white solid (501 mg): 1H NMR (300 MHz) δ 9.01 (d, J=1.9 Hz, 1H), 8.81 (s, 1H), 8.61 (d, J=1.9 Hz, 1H), 7.49-7.29 (m, 6H), 7.25-7.15 (m, 3H), 6.96 (dd, J=6.8, 4.8 Hz, 2H), 5.06 (s, 2H), 3.93 (dd, J=13.2, 6.9 Hz, 2H), 3.00 (t, J=7.0 Hz, 2H); ESIMS m/z 358.1 ([M+H]+).
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[C:12]2[C:11](=[O:22])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:23])(=[O:3])[CH3:2].[H-].[Na+].I[CH:27]([CH3:29])[CH3:28].CO>CN(C=O)C>[C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=2)[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:22][CH:27]([CH3:29])[CH3:28])[NH:6][C:5]=1[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)C1=C(C)Nc2ccnc(OC(C)C)c2C1c1ccc(C#N)cc1
Reaction time: 24 h

Procedure:
100 mg (0.32 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-benzonitrile are suspended in DMF (4 ml), and 14 mg (0.36 mmol) of sodium hydride (60% in mineral oil) are added. Then 34 μl (0.34 mmol) of 2-iodopropane are added to the dark red solution. The solution is stiffed at RT for 24 h, then mixed with methanol and purified by preparative HPLC. 18 mg (16% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH3:16])[C:9]=2[C:8](=[O:17])[N:7]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].[CH2:26]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:27]#[CH:28]>>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH3:16])[C:9]=2[C:8](=[O:17])[N:7]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])([CH3:23])[C:28]#[C:27][CH2:26][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCCC(C)=O)c(=O)c2c1ncn2CCC
Reactant: C#CCN1CCCCC1
Product: CCCCn1c(=O)n(CCCCC(C)(O)C#CCN2CCCCC2)c(=O)c2c1ncn2CCC
Yield: 58 %

Procedure:
The compound was prepared as oily substance in 58% yield using 3-butyl-1-(5-oxohexyl)-7-propylxanthine and N-(2-propynyl)piperidine as in Example 6C1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2].[CH3:21][O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.[Cu]Br>[CH2:18]([O:17][C:15]([C:7]1[N:8]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([O:22][CH3:21])=[O:31])[CH:25]=2)[C:9]2[C:14]([C:6]=1[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:20])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:16])[CH3:19]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)[nH]c2ccccc12
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1c(C(=O)OCC)n(-c2cccc(C(=O)OC)c2)c2ccccc12
Yield: 73.3 %

Procedure:
A solution of (2-ethoxycarbonyl-indol-3-yl)-acetic acid ethyl ester (J. Med. Chem. 1991, 34, 1283–1292, 2.2 g, 8.0 mmol), methyl-3-bromobenzoate (5.16 g, 24 mmol), anhydrous powdered K2CO3 (2.2 g, 16 mmol), and copper (I) bromide (2.3 g, 16 mmol) in N-methylpyrrolidone (NMP, 10 mL) was stirred at 170° C. overnight under inert atmosphere. The solvent was then removed by stream of nitrogen, and the residue was suspended in EtOAc (20 mL). The suspension was passed through a pad of silica gel using EtOAc-hexanes (1:2) as an eluent. The filtrate was concentrated in vacuo and purified by HPLC on LUNA 10μ silica column 25×250 mm with RI detector to afford 2.4 g of 3-ethoxycarbonylmethyl-1-(3-methoxycarbonyl-phenyl)-1H-indole-2-carboxylic acid ethyl ester as a white solid (73% yield): 1H NMR (CDCl3) δ 1.11 (t, J=7.3 Hz, 3H), 1.27 (t, J=7.1 Hz, 3H), 3.91 (s, 3H), 4.12–4.24 (m, 6H), 7.01–7.06 (m, 1H), 7.17–7.32 (m, 2H), 7.51–7.62 (m, 2H), 7.69–7.75 (m, 1H), 8.01–8.04 (m, 1H), 8.11–8.14 (m, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:13]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[CH3:29])=[C:12]([CH3:31])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].CO>C1COCC1>[CH3:3][C:4]1[C:13]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[CH3:29])=[C:12]([CH3:31])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(=O)CC3)ccc2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N2CCC(=O)CC2)cc1C(=O)Nc1c(C)ccc(C(=O)O)c1C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
A solution of aqueous 2N NaOH (1.00 ml) is added to a stirred solution of methyl 2,4-dimethyl-3-[[2-methyl-5-(4-oxo-1-piperidyl)benzoyl]amino]benzoate (0.12 g, 304.20 μmol) in THF:MeOH (2 ml:1 ml). After 16 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 6 with 1N HCl, and extracted with ethyl acetate. The organic layers are combined with aqueous layer and concentrated under reduced pressure. The resulting solids are dissolved in acetonitrile/H2O and lyophilized to afford the title compound as an off-white solid (58 mg, 50.12%). Mass spectrum (m/z): 381.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:5]([OH:7])=[O:6]
Reactant: CCOc1ccc(C(=O)OC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc(C(=O)O)cc1Cl
Yield: 78.1 %

Procedure:
To a stirred suspension of Methyl 3-chloro-4-(ethyloxy)benzoate (D6) (11.24 g, 52.4 mmol) in methanol (40 ml) was added 2M aq. NaOH (40 ml) and the resultant mixture was heated at 60° C. for 2 hours. The reaction mixture was partitioned between EtOAc and dilute hydrochloric acid. The organics were separated, dried and evaporated in vacuo to give the crude product. This material was triturated with ether to give the title compound as a white solid (8.21 g). MS (ES): C9H935ClO3 requires 200; found (MH+) 201.
Reaction SMILES: [C:1](#N)[C:2]([CH3:4])=[CH2:3].C1(CC(O)(C)C#N)[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[OH-].[K+]>CO.O>[OH:21][C:11]1[CH:12]=[C:13]2[C:3]3[C:17](=[CH:16][CH:15]=[CH:14]2)[C:18](=[O:20])[C:19]2[C:4](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:2]=3[CH:1]=1
Reactant: C=C(C)C#N
Reactant: CC(O)(C#N)Cc1cccc2c1C(=O)c1ccccc1C2=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1c2ccccc2-c2cc(O)cc3cccc1c23

Procedure:
There was obtained a distillate containing 35.7 g of methacrylonitrile, besides methanol and water. The distillation residue was then mushed or slurried with water, filtered, washed with water to neutrality, and finally well squeezed. The solid product thus obtained, consisting of 3-(1-anthraquinonyl)-2-hydroxy-2-methylpropionitrile: ##STR9## is suspended, still humid, in a solution of 500 cc of methanol containing 25 g of potassium hydroxide. This suspension was then reflux-heated for 1.5 hours and the red tinged solution thus obtained was freed of the insoluble impurities by filtering. It was then diluted with water up to 1.5 liters and then acidified with concentrated hydrochloric acid. Thereby was formed a yellow tinged precipitate which was filtered, washed with water to neutrality, and finally dried at 100° C. under vacuum until attaining a constant weight. In this way there were obtained 44.8 g of 2-hydroxybenzanthrone in the form of a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([OH:22])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:32])[F:31])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[OH-].[Na+].[F:35][C:36](F)([F:40])C(O)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:22][CH:36]([F:40])[F:35])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:31])[F:32])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(O)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nc(OC(F)F)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-4,6-dimethylpyrimidin-2-ol (290 mg, 0.607 mmol), benzyltriethylammonium chloride (6.9 mg, 0.0303 mmol), and 8N sodium hydroxide (2.4 mL) in tetrahydrofuran (2.4 mL) was stirred at room temperature under chloro(difluoro)methane atmosphere for 60 min. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture containing an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (84.0 mg, 0.159 mmol, 26%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH3:16])[CH3:2].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:22](Cl)=[O:23]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]([CH3:16])[C:22](=[O:23])[C:21]1[CH:20]=[C:19]([C:18]([F:33])([F:32])[F:17])[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=1)[CH3:2]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCc1ccccc1-c1ccncc1NC
Product: CCc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-ethyl-phenyl)-pyridin-3-yl]-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and a gradient of n-heptane:EtOAc (100:0 to 40:60) for the chromatographic purification. Light yellow solid (54%). MS (ESI): m/z=453.139 [M+H]+.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([C:33]2[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=2)=[O:32])[CH2:27][CH2:26]1>>[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:26][CH2:27][N:28]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([N:11]3[C@@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]3(=[O:15])=[O:16])=[CH:35][CH:34]=2)=[O:32])[CH2:29][CH2:30]1
Reactant: O=S1(=O)CC[C@H](COCc2ccccc2)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@@H](CO)CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 76.9 %

Procedure:
Using (R)-3-benzyloxymethylisothiazolidine 1,1-dioxide (370 mg) described in Preparation Example 10 and [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (643 mg) described in Preparation Example 108 and by the reaction and treatment in the same manner as in Example 32, the title compound (522 mg) was obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[N:13]O)[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CO.N.[H][H]>CCO.[Ni]>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([NH2:13])[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=NO)c1ccc2ncccc2c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: CO
Product: CC(N)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
To a solution of 1-quinolin-6-yl-ethanone oxime (4.54 g, 24.4 mmol) in EtOH (50 mL) was added methanol solution of NH3 (7N, 12 mL, 80 mmol). A slurry of Raney Nickel (washed 3× with EtOH) about 2 g was added followed by a hydrogen-filled balloon. The reaction was stirred at ambient temperature for 16 hours under hydrogen-filled balloon. The reaction mixture was filtered over a pad of celite and the mother liquor was concentrated to give quantitative 1-quinolin-6-yl-ethylamine (4.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]#[N:22])[CH:16]=[CH:17][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH:20][C:21]#[N:22])[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: N#CC=Cc1cccc(N)c1
Product: N#CC=Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1

Procedure:
5-Bromo-2-fluoro-benzoic acid (380 mg, 1.74 mmol) was coupled to aniline (88)(250 mg, 1.74 mmol) using Method C. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[C:12]([N:14]2[C:18](=[O:19])[NH:17][C:16]([CH3:20])=[N:15]2)[C:11]([F:21])=[CH:10][C:9]=1[Cl:22].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[C:12]([N:14]2[C:18](=[O:19])[N:17]([CH:2]([F:4])[F:3])[C:16]([CH3:20])=[N:15]2)[C:11]([F:21])=[CH:10][C:9]=1[Cl:22]
Reactant: COC(=O)c1cc(-n2nc(C)[nH]c2=O)c(F)cc1Cl
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl
Yield: 109 %

Procedure:
An excess of chlorodifluoromethane (97 g) was bubbled into a mixture of triazolinone from step 2 (7.04 g, 24.6 mmol), tetrabutylammonium bromide (9.67 g, 30.0 mmol), potassium carbonate (16.6 g, 122 mmol) and dimethylformamide (200 ml) in such a way that T<36° C. over a period of 30 minutes. The mixture was cooled and filtered. The filtrate was concentrated under reduced presssure and the residue partitioned between water and methylene chloride. The organic layer was washed with water, dried and concentrated under reduced pressure to give a dark oil (9.00 g), which was chromatographed on silica gel (eluent: ethyl acetate/hexane) to give the title compound. Yield: 1.48 g (17.9%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:19])[S:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH3:18])[CH:10]=2)=[O:5])C.[NH2:20][CH2:21][C:22]([O-:24])=[O:23].[Na+]>COCCO>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[S:8][C:7](=[O:19])[C:6]=1[C:4]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:5]
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c2ccc(OC)cc2sc1=O
Agent: [Na+]
Solvent: COCCO
Product: COc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)sc2c1
Yield: 78 %

Procedure:
A mixture of 4-hydroxy-7-methoxy-2-oxo-2H-thiochromene-3-carboxylic acid ethyl ester (47 mg, 0.17 mmol) and sodium glycinate (81 mg, 0.84 mmol) in 2-methoxyethanol (5.6 mL) was refluxed overnight (20 h). The reaction mixture was concentrated, and the crude residue dissolved in water (60 mL), acidified to pH 3-4 using 1 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide [(4-hydroxy-7-methoxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (41 mg). MS ESI(−) m/e: 308.06 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.I[CH2:30][CH:31]([CH3:33])[CH3:32]>C1(C)C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Ag-]=O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]([CH2:22][O:23][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)CO
Reactant: CC(C)CI
Agent: O=[Ag-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: Cc1ccccc1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)COCC(C)C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
250 mg (0.64 mmol) of 8-[(2,6-difluorobenzyl)oxy]-N-(1,3-dihydroxy-propan-2-yl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide and 4.94 g (26.83 mmol) of 1-iodo-2-methylpropane were initially charged in dry toluene, 1.87 g (7.66 mmol) of silver(I) oxide and 118 mg (0.32 mmol) of tetra-n-butylammonium iodide were added and the mixture was stirred at 40° C. overnight. The reaction mixture was filtered through Celite, the filter cake was washed thoroughly, the filtrate was concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The crude product was then purified by preparative thick-layer chromatography (mobile phase: dichloromethane:methanol=20:1). This gave 13 mg of the target compound (4.5% of theory, purity 100%).
Reaction SMILES: [NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([NH:12][C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH3:21][C:22]1[N:27]=[C:26]([C:28](O)=[O:29])[CH:25]=[N:24][CH:23]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]([NH:12][C:4]12[CH2:10][CH:8]3[CH2:7][CH:6]([CH2:11][C:2]([NH:1][C:28]([C:26]4[CH:25]=[N:24][CH:23]=[C:22]([CH3:21])[N:27]=4)=[O:29])([CH2:9]3)[CH2:3]1)[CH2:5]2)=[O:14]
Reactant: NC12CC3CC(C1)CC(NC(=O)c1ccccn1)(C3)C2
Reactant: Cc1cncc(C(=O)O)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cncc(C(=O)NC23CC4CC(CC(NC(=O)c5ccccn5)(C4)C2)C3)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a round bottom flask was added pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-amide (3.10 g, 11.0 mmol, Intermediate 2), 6-methylpyrazine-2-carboxylic acid (1.83 g, 13.3 mmol; RihaChem, Kostalov, Czech Republic) and methylene chloride (120 mL). To the solution was then added PyBOP® (6.90 g, 13.3 mmol) followed by triethylamine (3.85 mL, 27.6 mmol) and the reaction was stirred for two hours at room temperature. The reaction was transferred to a 500-mL reparatory funnel with methylene chloride (50 mL) and saturated aqueous sodium bicarbonate (150 mL), and extracted with methylene chloride. The organic layer was separated and the aqueous layer was extracted again with methylene chloride (2×75 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a RP-HPLC/MS purification system (Gradient: acetonitrile in water, 27-95%, in 3.5 min with a shallow gradient from 30-60% between 0.75-3.4 min and a cycle time of 5 min. Flow rate: 100 mL/min. Mobile phase additive: 38 mM of ammonium acetate. Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan). Mobile phase and column temperature: 50° C.). Fractions were then concentrated under reduced pressure to remove most of the acetonitrile, the resulting aqueous layer was made basic with solid sodium carbonate (pH>10) and the aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 3.21 g (74%) of the title compound, 6-methyl-pyrazine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide, as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.17 (s, 1H), 8.58 (s, 1H), 8.54-8.50 (m, 1H), 8.17 (dt, J=7.8, 1.0 Hz, 1H), 8.06 (br s, 1H), 7.85 (td, J=7.7, 1.7 Hz, 1H), 7.77 (br s, 1H), 7.42 (ddd, J=7.6, 4.8, 1.3 Hz, 1H), 2.61-2.57 (m, 5H), 2.40-2.28 (m, 4H), 2.27-2.19 (m, 2H), 2.18-2.08 (m, 4H), 1.78-1.68 (m, 2H). ESI-MS m/z: 392.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:7]=1.[C:13]([O:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](B(O)O)=[CH:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:10]1[CH:11]=[CH:12][C:8]([C:6]2[CH:7]=[C:2]([C:22]3[C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH:21]=3)[CH:3]=[N:4][CH:5]=2)=[CH:9]1
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)c2ccccc21
Reactant: Brc1cncc(-c2ccsc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1cc(-c2cncc(-c3ccsc3)c2)c2ccccc21

Procedure:
A deoxygenated solution of 3-bromo-5-thiophen-3-yl-pyridine (2.50 g, 10.4 mmol, 1 equiv), 1-(t-butyloxycarbonyl)-3-indoleboronic acid (4.073 g, 15.6 mmol, 1.50 equiv), Pd(PPh3)4 (601 mg, 0.520 mmol, 0.0500 equiv), and 2.0 M Na2CO3 (10.4 mL, 20.8 mmol, 2.00 equiv) in dioxane (120 ml) was heated under argon at reflux for 20 h. The reaction mixture was allowed to cool, then partitioned between water (500 mL) and ethyl acetate (3×150 mL). The combined organic layers were washed sequentially with water (500 mL) and brine (500 ml), then dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (40% ethyl acetate in hexane) to afford 3-(5-thiophen-3-yl-pyridin-3-yl)-1-(t-butyloxycarbonyl)-indole as a colorless oil. The oil was dissolved in ethyl acetate (100 ml), and the resulting solution was cooled to 0° C., then saturated with HCl gas. The solution was allowed to warm to 23° C. and stirred for 30 minutes. The precipitate was filtered and washed with ethyl ether (50 mL). The solid was then partitioned between ethyl acetate (150 mL) and aqueous saturated NaHCO3 solution (150 mL). The organic layer was dried over Na2SO4 and concentrated to give compound 1 (3-(5-thiophen-3-yl-pyridin-3-yl)-indole) as a white solid.