Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]([C:10]1[O:11][C:12]2[C:18]([N:19]3[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]3=[O:31])=[C:17]([F:32])[CH:16]=[C:15]([Cl:33])[C:13]=2[N:14]=1)([CH3:9])[CH3:8].O>C(Cl)Cl>[OH:6][C:7]([C:10]1[O:11][C:12]2[C:18]([N:19]3[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]3=[O:31])=[C:17]([F:32])[CH:16]=[C:15]([Cl:33])[C:13]=2[N:14]=1)([CH3:9])[CH3:8]
Reactant: COC(C)(C)c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(C(C)(C)O)oc23)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.4 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 3.8 mL (3.8 mmole) of 1M boron tribromide (in methylene chloride) in 50 mL of methylene chloride was cooled to about -40° C., and a solution of 0.6 gram (2.6 mmole) of 3-[2-(1-methoxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione in 50 mL of methylene chloride was added dropwise at such a rate as to maintain the reaction mixture temperature below -30° C. Upon completion of the addition the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 18 hours. At the conclusion of this period the reaction mixture was poured into water and thoroughly extracted with methylene chloride. The combined extracts were washed with an aqueous saturated sodium chloride solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a brown oil, which was subjected to column chromatography on silica gel. Elution was with 1:4 ethyl acetate to heptane. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.3 gram of 3-[2-(1-hydroxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][Li].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[N:5]1>C1COCC1>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[O:15])[CH3:1])=[N:5]1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1nn(C)c2ccccc12

Procedure:
Methyl lithium (1.58M solution in ether; 13.8 ml) was added dripwise to a stirred, cold (-60°) solution of 1-methyl-1H-indazole-3-carboxylic acid (1.77 g) in dry THF (60 ml) under nitrogen and stirring was continued while warming to 0° over 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (50 ml), and the layers were separated. The aqueous layer was further extracted with dichloromethane (2×50 ml ) and the combined organic layers were washed with brine (2×50 ml ), dried and evaporated in vacuo. The residual solid (1.8 g) was purified by FCC eluting with System B (1:4) to give the title compound (1.3 g, m.p. 86°-88°.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5](=O)[CH2:6][CH:7]([CH3:12])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:3].[C:14]([C:18]1[CH:23]=[C:22]([SH:24])[CH:21]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]=1[OH:29])([CH3:17])([CH3:16])[CH3:15]>CO>[C:14]([C:18]1[CH:23]=[C:22]([S:24][C:5]([S:24][C:22]2[CH:21]=[C:20]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:19]([OH:29])=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:23]=2)([CH2:6][CH:7]([CH3:12])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:4][CH:2]([CH3:3])[CH3:1])[CH:21]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]=1[OH:29])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)CC(=O)CC(C)CC(C)C
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Product: CC(C)CC(C)CC(CC(C)C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 9.22 grams of 2,6,8-trimethylnonan-4-one, 23.84 grams of 2,6-di-tert-butyl-4-mercaptophenol, and 150 ml of methyl alcohol. The product is purified by flask chromatography to give a clear syrup whose proton NMR spectrum is consistent with the desired structure.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:31]=[C:32]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:39][S:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:28])([F:40])[F:41])[CH:31]=3)(=[O:38])=[O:37])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)c1cccc(C(F)(F)F)c1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 3-(trifluoromethyl) benzenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (35%); 1H NMR (d6-DMSO) δ 8.22-8.08 (m, 3H), 7.86 (t, J=7.7 Hz, 1H), 7.42-7.07 (m, 13H), 6.84 (d, J=8.0 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 562 (M+H+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[C:21]([C:28]3[NH:36][C:35]4[CH2:34][CH2:33][NH:32][C:31](=[O:37])[C:30]=4[CH:29]=3)[CH:22]=[CH:23][CH:24]=2)[N:19]=1>C1COCC1>[O:37]=[C:31]1[C:30]2[CH:29]=[C:28]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:20]=3[N:19]=[C:18]([O:1][C@H:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]3)[CH:27]=[CH:26]4)[NH:36][C:35]=2[CH2:34][CH2:33][NH:32]1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-tert-Butyl 3-hydroxypiperidine-1-carboxylate (Astatech Inc., Bristol, Pa.; 406 mg, 2.02 mmol) was added to a suspension of NaH (81 mg, 2.02 mmol) in THF (2.5 mL) and the resulting suspension was stirred at RT for 10 min. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 75 mg, 0.25 mmol) was then added and the resulting suspension was stirred at RT for 5 min, then heated at 70° C. for 1.25 h. The mixture was cooled to RT and partitioned between EtOAc (60 mL) and saturated aq. NH4Cl (20 mL). The organic layer was separated, sequentially washed with water (20 mL) then brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give (S)-tert-butyl 3-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)oxy)piperidine-1-carboxylate as a light yellow solid: m/z (ESI, +ve ion) 463.1 (M+H)+. The material was used in the subsequent step without further purification.
Reaction SMILES: CN1CCOCC1.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2([C:21]([OH:23])=O)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1.Cl.Cl.[F:26][C:27]1[C:32]2[C:33](=[O:40])[O:34][C:35]3([CH2:39][CH2:38][NH:37][CH2:36]3)[C:31]=2[CH:30]=[CH:29][N:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CN(C)C=O>>[F:26][C:27]1[C:32]2[C:33](=[O:40])[O:34][C:35]3([CH2:39][CH2:38][N:37]([C:21]([C:18]4([C:11]5[C:12]6[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=6)[N:8]=[CH:9][CH:10]=5)[CH2:19][CH2:20]4)=[O:23])[CH2:36]3)[C:31]=2[CH:30]=[CH:29][N:28]=1
Reactant: O=C(O)C1(c2ccnc3ccccc23)CC1
Reactant: O=C1OC2(CCNC2)c2ccnc(F)c21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C1OC2(CCN(C(=O)C3(c4ccnc5ccccc45)CC3)C2)c2ccnc(F)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl in dioxane (4.0 M, 1 mL) was added to tert-butyl 4-fluoro-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidine]-1′-carboxylate (25.8 mg, 0.0000837 mol). The reaction mixture was stirred at room temperature for 30 minutes before the volatiles was removed to afford the free amine (hydrochloric acid salt), which was subsequently used in the coupling reaction. 4-Methylmorpholine (50 μL, 0.0004 mol) was added to a mixture of 1-quinolin-4-ylcyclopropanecarboxylic acid (17.8 mg, 0.0000837 mol), 4-fluoro-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one dihydrochloride (23.5 mg, 0.0000837 mol), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (45.7 mg, 0.0000879 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol). The reaction mixture was stirred at room temperature for 2 hours. The crude product was purified by prep-LCMS. LC/MS: 402.1 (M+H+).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][C:18]=2[C:28]([O:30]CC)=[O:29])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:19][C:18]=2[C:28]([OH:30])=[O:29])[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2sc(-c3ccccc3)nc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
1 N NaOH (5.4 mL) was added to a solution of ethyl 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-phenylthiazole-4-carboxylate (1.50 g, 3.6 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 16 h then concentrated in vacuo. H2O was added and the mixture was washed with EtOAC. The pH of the aqueous layer was adjusted to 5 by the addition of 1N HCl and the resulting ppt was collected by filtration, washed with H2O, and dried to give 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-phenylthiazole-4-carboxylic acid as a white solid (0.9 g, 64% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]2[CH2:13][CH:14]([CH2:17]OS(C)(=O)=O)[CH2:15][CH2:16][CH:9]2[CH2:8]1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C.O>[N:23]([CH2:17][CH:14]1[CH2:13][N:10]2[CH2:11][CH2:12][N:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:8][CH:9]2[CH2:16][CH2:15]1)=[N+:24]=[N-:25]
Reactant: CS(=O)(=O)OCC1CCC2CN(c3ncccn3)CCN2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1CCC2CN(c3ncccn3)CCN2C1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A solution containing methanesulfonic acid 2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl ester (1 eq., see subpart (b) above) and sodium azide (2 eq.) in DMF was stirred at around 90° C. for 24 hours. The solution was cooled to room temperature, diluted with water, and extracted with methylene chloride. The combined organic layers was washed with brine, dried over Na2SO4, filtered, and concentrated to give the corresponding azide as yellow oil. This material was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH3:23])=[C:19](/[F:22])\[CH2:20][OH:21])[C:3]=1[O:24][CH2:25][CH3:26].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH3:23])=[C:19](/[F:22])\[CH:20]=[O:21])[C:3]=1[O:24][CH2:25][CH3:26]
Reactant: CCOc1c(/C(C)=C(/F)CO)cc2c(c1Br)C(C)(C)CC=C2C(C)(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCOc1c(/C(C)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)(C)C

Procedure:
As described in General Procedure H-1, (2E)-3-(4-bromo-8-tert-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-en-1-ol (Compound A-141, 45 mg, 0.11 mmol), tetrapropylammonium perruthenate (10 mg, 0.028 mmol) and 4-methylmorpholine N-oxide (31 mg, 0.26 mmol) were reacted in acetonitrile and dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10])([CH3:5])[CH3:4].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[CH2:29]Br>CN(C=O)C>[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]2[C:23]=1[CH2:29][N:11]([C:9]([C:8]1[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:7]=1[O:6][CH:3]([CH3:5])[CH3:4])=[O:10])[CH2:21]2
Reactant: Fc1cccc(CBr)c1CBr
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2cccc(F)c2C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
To a RT suspension of 0.61 mmol sodium hydride (50% in mineral oil) in 0.5 ml dry DMF, a solution of 0.29 mmol 2-Isopropoxy-5-methanesulfonyl-benzamide (example B20) in 1 ml dry DMF was added dropwise. After 15 minutes at RT and 15 minutes at 50° C., the reaction mixture was cooled to 0° C., and treated by a solution of 0.29 mmol 1,2-Bis-bromomethyl-3-fluoro-benzene (CAS: 62590-16-3) in 1 ml dry DMF. The reaction mixture was allowed to warm to RT and stirred for 15 minutes then cooled to 0° C., quenched with water and extracted with ethylacetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (27% yield). MS (m/e): 378.3 [M+H+], 100%)
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[CH:11]([NH:13][NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:26][CH3:27])=[C:19]([CH2:21][CH2:22][C:23]([OH:25])=O)[CH:20]=1)=[O:12].[NH2:28][C:29]1[CH:37]=[CH:36][C:32]2[NH:33][N:34]=[N:35][C:31]=2[CH:30]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:33]1[C:32]2[CH:36]=[CH:37][C:29]([NH:28][C:23](=[O:25])[CH2:22][CH2:21][C:19]3[CH:20]=[C:15]([NH:14][NH:13][CH:11]=[O:12])[CH:16]=[CH:17][C:18]=3[O:26][CH3:27])=[CH:30][C:31]=2[N:35]=[N:34]1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: COc1ccc(NNC=O)cc1CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(NNC=O)cc1CCC(=O)Nc1ccc2[nH]nnc2c1

Procedure:
Anhydrous N-hydroxybenzotriazole (1.3 g) was added to a cooled solution of 3-[5-(2-formylhydrazino)-2-methoxyphenyl]propionic acid (1.2 g) and 5-aminobenzotriazole (0.67 g, 0.005 mole) in dry dimethylformamide (10 ml). A solution of dicyclohexylcarbodi-imide (1.1 g) was added dropwise to the solution of reactants at such a rate that the temperature was kept at 0°.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([N:24]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=3[O:39][CH3:40])[C:25]3[S:29][N:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[N:14]([CH3:41])[CH:13]=1.[N:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:40][O:39][C:32]1[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:31]=1[CH2:30][N:24]([C:25]1[S:29][N:28]=[CH:27][N:26]=1)[S:21]([C:17]1[CH:16]=[C:15]2[C:20]([C:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]=3[C:45]3[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=3)=[CH:13][N:14]2[CH3:41])=[CH:19][CH:18]=1)(=[O:23])=[O:22]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)cn(C)c3c2)c(OC)c1
Reactant: OB(O)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccncc4)cn(C)c3c2)c(OC)c1

Procedure:
A microwave vial was charged with 3-(2-bromo-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.050 g, 0.075 mmol), pyridin-4-ylboronic acid (0.018 g, 0.150 mmol), potassium phosphate (0.056 g, 0.262 mmol), and Pd(AmPhos)2Cl2 (5.30 mg, 7.49 μmol). The vial was flushed with Ar, then 1,4-dioxane (0.375 ml) and water (0.125 ml) were added in sequence. The vial was sealed and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered and concentrated. The material was purified via column chromatography (Redi-Sep Gold (Teledyne Isco, Lincoln, Nebr.) 12-g, gradient elution 0 to 100% EtOAc/Heptane) to afford N-(2,4-dimethoxybenzyl)-1-methyl-3-(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide as a yellow solid. The solid was dissolved in DCM (0.5 ml) and TFA (0.5 ml, 6.49 mmol), and the resulting mixture was stirred for 15 min. The mixture was concentrated in vacuo. The residue was dissolved in acetonitrile, and passed through a PEAX ion exchange column. The column was flushed several times with acetonitrile, then the product was liberated by flushing several times with an 1M HCl solution in 15% MeOH/EtOAc. The solution was concentrated to afford 1-methyl-3-(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.55 (d, J=6.1 Hz, 2 H), 8.44 (s, 1 H), 7.97-7.90 (m, 2 H), 7.87 (s, 1 H), 7.80 (d, J=8.0 Hz, 1 H), 7.56-7.49 (m, 3 H), 7.34 (d, J=1.5 Hz, 2 H), 3.85 (s, 3 H). m/z (ESI) 516.0 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[C:22]1([NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].FC(F)(F)C(O)=O>O1CCCC1>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:29][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2](=[O:1])[NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccccc1N
Reactant: O=C(COc1ccc(C(=O)O)cc1)NCc1cccnc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1NC(=O)c1ccc(OCC(=O)NCc2cccnc2)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
0.34 g (2.1 mmole) of N,N′-carbonyldiimidazole was added to a tetrahydrofuran (10 ml) suspension including 0.6 g (2.1 mmole) of 4-{2-oxo-2-[(pyridin-3-ylmethyl)amino]ethoxy}benzoic acid, followed by stirring at 45° C. for 1 hour. After cooling to room temperature, 2.1 g (19.4 mmole, 8 equivalents) of 1,2-phenylenediamine and 0.4 ml of trifluoroacetic acid were added, and reaction was further carried out for 15 hours. After completion of the reaction, a post-treatment was performed in the same manner as in Example 6 to obtain 0.67 g (yield: 53%) of N-(2-aminophenyl)-4-{2-oxo-2-[(pyridin-3-ylmethyl)amino]ethoxy}-benzamide.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34](O)(=[O:39])[CH2:35][CH2:36][C:37]#[CH:38]>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[C:34](=[O:39])[CH2:35][CH2:36][C:37]#[CH:38])=[CH:32][CH:33]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#CCCC(=O)O
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Product: C#CCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(OCC(=O)O)cc1

Procedure:
The titled compound was prepared following the procedure H using methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}acetate and pent-4-ynoic acid as a yellow oil (99%). HPLC, Rt: 5.63 min (Purity: 98.6%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[N:38]([CH:44]1[CH2:49][CH2:48][C:47](=[O:50])[NH:46][C:45]1=[O:51])[C:37]2=[O:52].CCOC(C)=O>CN(C)C=O>[O:51]=[C:45]1[CH:44]([N:38]2[C:37](=[O:52])[C:36]3[C:40](=[CH:41][CH:42]=[C:34]([CH2:33][NH:32][C:10](=[O:12])[C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:14][CH:13]=4)[CH:35]=3)[C:39]2=[O:43])[CH2:49][CH2:48][C:47](=[O:50])[NH:46]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
A stirred mixture of 4-ethylsulfonylbenzoic acid (0.64 g, 3.00 mmol) and CDI (0.51 g, 3.15 mmol) in N,N-dimethylformamide (34 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (1.15 g, 3.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (150 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc/hexanes, gradient). The product fractions were combined and concentrated to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-ethane sulfonyl-benzamide as a white solid (0.63 g, 44% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.66 min (97.99%); mp: 182-184° C.; 1H NMR (DMSO-d6) δ 1.11 (t, J=7.4 Hz, 3H), 2.00-2.18 (m, 1H), 2.54-2.68 (m, 2H), 2.80-2.99 (m, 1H), 3.35 (q, J=7.4 Hz, 2H), 4.68 (d, J=5.7 Hz, 2H), 5.15 (dd, J=5.3, 12.8 Hz, 1H), 7.77-7.97 (m, 3H), 7.98-8.07 (m, 2H), 8.08-8.25 (m, 2H), 9.49 (t, J=5.8 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 7.06, 21.99, 30.93, 42.77, 49.02, 122.08, 123.58, 128.03, 128.32, 129.90, 131.63, 133.53, 138.50, 140.85, 147.11, 165.24, 166.96, 167.10, 169.82, 172.75; LCMS: MH=484; Anal Calcd for C23H21N3O7S+0.45H2O: C, 56.19; H, 4.49; N, 8.55. Found: C, 55.87; H, 4.47; N, 8.28.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:22][NH:23][CH3:24]>C(O)C>[CH3:22][N:23]([CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:24]
Reactant: COC(=O)c1cccc2nc(-c3cccc(CBr)c3)oc12
Reactant: CNC
Solvent: CCO
Product: COC(=O)c1cccc2nc(-c3cccc(CN(C)C)c3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.2 %

Procedure:
Methyl 2-(3-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate (70 mg, 0.2 mmol) and dimethylamine (72 mg, 1.6 mmol) were added to ethanol (30 mL) and the mixture was stirred at room temperature for 1 hr. The resulting mixture was evaporated under reduced pressure to obtain methyl 2-(3-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (74 mg, yield 86%). LC-MS (ESI) m/z 310 [M+1]+.