Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][C:18]2[CH:29]=[CH:28][CH:27]=[CH:26][C:19]=2[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1>O=[Mn]=O.O1CCOCC1>[F:1][C:2]1[C:3]([NH:17][C:18]2[CH:29]=[CH:28][CH:27]=[CH:26][C:19]=2[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CC(C)NC(=O)c1ccccc1Nc1nc(Nc2ccc(CO)cc2)ncc1F
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1ccccc1Nc1nc(Nc2ccc(C=O)cc2)ncc1F
Yield: 96.1 %

Procedure:
A 50-mL of round bottom flask was charged with 2-[(5-fluoro-2-{[4-(hydroxymethyl)phenyl]amino}-4-pyrimidinyl)amino]-N-(1-methylethyl)benzamide (200 mg, 0.5 mmol, 1.0 eq) and dioxane (20 mL). MnO2 (217 mg, 2.5 mmol, 5.0 eq) was added slowly to this solution. Upon completion of the addition, the reaction mixture was heated at reflux for 16 h. The reaction mixture was filtered through celite and the solvent was evaporated to produce the desired product (189 mg, 48% yield) which was found to be 82% pure by HPLC. MS: M(C21H20FN5O2)=393.42, (M+H)+=394. This crude material was used for next step without further purification.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:2]=1.Br[C:30]1[CH:31]=[C:32]([Si:36]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([Br:55])[CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:34][CH:35]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C(C)=CC=CC=1.O.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]>[Br:55][C:51]1[CH:50]=[C:49]([Si:36]([C:32]2[CH:31]=[C:30]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:4]4[C:5]5[S:6][C:7]6[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=6[C:9]=5[CH:1]=[CH:2][CH:3]=4)[CH:15]=3)[CH:35]=[CH:34][CH:33]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:54]=[CH:53][CH:52]=1
Reactant: CC1(C)OB(c2cccc(-c3cccc4c3sc3ccccc34)c2)OC1(C)C
Reactant: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(Br)c2)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(-c3cccc(-c4cccc5c4sc4ccccc45)c3)c2)c1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A mixture solution of 2-(3-(dibenzo[b,d]thiophen-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.0 g, 15.53 mmol), bis(3-bromophenyl)diphenylsilane (19.19 g, 38.8 mmol), Pd2(dba)3 (0.28 g, 0.31 mmol), SPhos (0.26 g, 0.62 mmol) and K3PO4 (3.30 g, 15.53 mmol) in xylene (150 mL) and water (15 mL) was refluxed under nitrogen at 120° C. overnight. After cooling to room temperature, the reaction mixture was quenched with water, extracted with DCM, washed with brine and water, and dried over Na2SO4. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane:DCM (9.5:0.5 to 9:1, v/v) as eluent. The crude product was dissolved in DCM, precipitated with methanol, and filtered to yield (3-bromophenyl)(3′-(dibenzo[b,d]thiophen-4-yl)-[1,1′-biphenyl]-3-yl)diphenylsilane (3.2 g, 30.6%) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[Br:19])=[O:11].Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1>>[Br:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[C:10]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:9])[C@@H:3]1[CH2:2][NH:1][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1)=[O:11]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1ccc(Br)c(C(=O)N2CCC[C@H](C)[C@@H]2CN)c1
Product: Cc1ccc(Br)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example 11 starting with rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(2-bromo-5-methylphenyl)methanone and 2-chloro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 470, 472, [M]+, [M+2]+.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[N+:6]([C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[C:12]([NH:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)=[O:13])([O-:8])=[O:7].[OH-].[CH2:25]([N+:29]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[N+:6]([C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[C:12]([NH:14][CH2:15][C:16]1[S:17][C:18]([S:2]([O-:5])(=[O:4])=[O:3])=[CH:19][CH:20]=1)=[O:13])([O-:8])=[O:7].[CH2:38]([N+:29]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:39][CH2:40][CH3:41]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(NCc1cccs1)c1cccc([N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCc1ccc(S(=O)(=O)[O-])s1)c1cccc([N+](=O)[O-])c1
Reaction time: 3 h
Yield: 97.9 %

Procedure:
Chlorosulfonic acid (5.62 mL, 84 mmol) was dissolved in 20 mL CH2Cl2 and added to a solution of 3-Nitro-N-(thien-2-ylmethyl)benzamide (11.0 g, 42 mmol) in 100 mL CH2Cl2 under vigorous stirring. A gummy solid was formed and the reaction mixture was stirred for 3 h. The reaction was quenched with ice, and ice cold NaHCO3 solution was added to reach pH8.5. The aqueous layer was washed twice with CH2Cl2. Tetrabutylammoniumhydroxide (40% in water) (32 mL, 50 mmol) was added to the aqueous layer, while a solid was formed. The precipitate was extracted into CH2Cl2 and the aqueous layer was washed 3× with CH2Cl2. The combined organic layers were dried over MgSO4 and evaporated to dryness to afford a slightly colored foam of Tetrabutylammonium 5-{[(3-Nitrobenzoyl)amino]methyl}thiophene-2-sulfonate (24 g, 97%). NMR spectra indicated pure compound, which was used for the following chlorination step.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([O:13]C)[CH:6]=[C:7]2[C:12]=1[CH:11]=[N:10][CH:9]=[CH:8]2>O>[Br:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]2[C:12]=1[CH:11]=[N:10][CH:9]=[CH:8]2
Reactant: COc1cc(Br)c2cnccc2c1
Agent: Br
Solvent: O
Product: Oc1cc(Br)c2cnccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
An aqueous hydrobromic acid (180 mL) solution of Intermediate 6 (30 g) was stirred at 130° C. for 38 hours. The resulting mixture was stirred at room temperature for approx. 10 minutes followed by the addition of water (300 mL) and the precipitate was collected by filtration and dried to give the title compound (21 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([C:20]([OH:22])=O)[O:17][N:16]=1.F[B-](F)(F)F.[N:28]1(OC(N(C)C)=[N+](C)C)[C:32]2[CH:33]=[CH:34][CH:35]=CC=2N=[N:29]1.C(N(CC)C(C)C)(C)C.Cl.NN1CCCC1>CN(C=O)C>[N:28]1([NH:29][C:20]([C:18]2[O:17][N:16]=[C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])[CH:19]=2)=[O:22])[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)O)on1
Agent: Cl
Agent: F[B-](F)(F)F
Agent: NN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NN2CCCC2)on1
Reaction time: 4 h
Yield: 73.3 %

Procedure:
To a solution of 3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (120 mg, 0.4 mmol) in DMF (5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (192 mg, 0.6 mmol), N,N-diisopropyl ethyl amine (340 μL, 2.0 mmol) and N-aminopyrrolidine HCl (64 mg, 0.52 mmol). The resulting reaction mixture was for 4 h at room temperature. Concentration and purification by chromatography (silica, dichloromethane:methanol=1:0 to 4:1) afforded the title compound (108 mg, 73%) as a colourless oil. MS: m/e=369.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Br:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].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.O>[Br:32][C:33]1[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][C:34]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Br
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)nccc3c2)c(OC)c1

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.075 g, 0.158 mmol), (2-bromo-4-(trifluoromethyl)phenyl)boronic acid (0.064 g, 0.236 mmol), tetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.016 mmol), and potassium carbonate (0.109 g, 0.788 mmol). Dioxane (1.182 ml) and water (0.394 ml) were added, the vial was flushed with argon and 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 dried with sodium sulfate, filtered, and concentrated. The material was purified by silica gel chromatography (12 g column, gradient elution 0 to 50% EtOAc:Heptane) to afford 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a white solid. m/z (ESI) 664.1 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])(C)(C)C.C(O[C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34][N:33]=2)[CH:27]=1)=O)(C)(C)C>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34][N:33]=4)[CH:27]=3)[CH2:23][C:22](=[O:39])[NH:15][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Product: Cc1cc(-c2cccc(C3=Nc4ccc(Cl)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) (121 mg, 0.5 mmol) and 3-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K41) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (37 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[CH2:6][C:7]1[NH:15][C:14]2[C:9](=[N:10][C:11]([O:16][CH3:17])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[CH2:6][C:7]1[N:15]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=2)[C:14]2[C:9](=[N:10][C:11]([O:16][CH3:17])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1cc2nc(OC)ccc2[nH]1
Reactant: ClCc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1cc2nc(OC)ccc2n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
3-(5-Methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)-2,2-dimethyl-propionic acid ethyl ester (0.350 g, 1.27 mmol), 4-chlorobenzyl chloride (0.306 g, 1.90 mmol), Cs2CO3 (0.825 g, 2.53 mmol), and tetrabutylammonium iodide (0.094 g, 0.25 mmol) were suspended in DMF (˜1 mL) and stirred at 60° C. overnight under N2. DMF was removed in vacuo, the residue was dissolved in ether and water, and the aqueous layer was extracted three times with ether. The combined organic layers were washed twice with water, once with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica gel (0-100% EtOAc in hexanes) to obtain the desired ester.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=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:12]([C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:11][N:10]=4)=[O:14])[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)nc1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 32.3 %

Procedure:
A stirred mixture of 5-ethanesulfonyl-pyridine-2-carboxylic acid (0.34 g, 1.60 mmol) and CDI (0.27 g, 1.70 mmol) in N,N-dimethylformamide (15 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 (0.61 g, 1.60 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×75 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc/hexanes, gradient, product eluted at 80-90% EtOAc). The product fractions were combined and concentrated to give 5-ethanesulfonyl-pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.25 g, 32% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 6.15 min (96.20%); mp: 265-267° C.; 1H NMR (DMSO-d6) δ 1.15 (t, J=7.4 Hz, 3H), 2.00-2.20 (m, 1H), 2.52-2.67 (m, 2H), 2.77-3.01 (m, 1H), 3.48 (q, J=7.4 Hz, 2H), 4.69 (d, J=6.2 Hz, 2H), 5.14 (dd, J=5.4, 12.7 Hz, 1H), 7.73-8.04 (m, 3H), 8.29 (d, J=8.3 Hz, 1H), 8.49 (dd, J=2.3, 8.1 Hz, 1H), 9.10 (d, J=1.7 Hz, 1H), 9.86 (t, J=6.3 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 6.83, 21.99, 30.93, 42.58, 49.01, 49.34, 122.17, 122.68, 123.54, 129.87, 131.59, 133.63, 137.04, 138.13, 147.09, 147.60, 153.38, 163.02, 166.97, 167.12, 169.80, 172.72; LCMS: MH=485; Anal Calcd for C22H20N4O7S: C, 54.54; H, 4.16; N, 11.56. Found: C, 54.82; H, 3.92; N, 11.57.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:34][CH3:35])C1C=CC=CC=1.CS(O)(=O)=O>FC(F)(F)C(O)=O>[CH3:26][C:24]1[CH:25]=[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:34][CH3:35])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:22][C:23]=1[CH3:27]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 109.1 %

Procedure:
3-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,2′]bipyridine (compound 337) (497 mg) was dissolved in trifluoroacetic acid (5 ml) to prepare a solution. Methanesulfonic acid (0.5 ml) was added to the solution, and the mixture was stirred at 70° C. for 1.5 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. An aqueous sodium hydrogencarbonate solution was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (437 mg, yield 100%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:31][C:32]1[S:33][C:34]([C:38]([OH:42])([C:40]#[CH:41])[CH3:39])=[C:35]([CH3:37])[N:36]=1>>[C:26]([O:25][C@@H:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:41]#[C:40][C:38]([C:34]3[S:33][C:32]([CH3:31])=[N:36][C:35]=3[CH3:37])([OH:42])[CH3:39])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([OH:22])=[O:21])([CH3:27])([CH3:28])[CH3:29]
Reactant: C#CC(C)(O)c1sc(C)nc1C
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Product: Cc1nc(C)c(C(C)(O)C#Cc2ccc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c4ccc(Cl)cc4)c3c2)s1

Procedure:
(2S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-(2,4-dimethylthiazol-5-yl)-3-hydroxybut-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid was prepared by the method in Example 8 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate and 2-(2,4-dimethylthiazol-5-yl)but-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.78 (d, J=8 Hz, 1H), 7.70 (s, 1H), 7.58 (m, 3H), 7.43 (d, J=8 Hz, 1H), 7.32 (m, 2H), 5.18 (s, 1H), 2.64 (s, 3H), 2.61 (s, 3H), 2.47 (s, 3H), 1.82 (s, 3H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H32ClNSO4: 562.2. found: 562.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Cl[C:45]1[N:50]=[CH:49][C:48]([N:51]=[S:52]([CH3:57])([N:54]([CH3:56])[CH3:55])=[O:53])=[CH:47][N:46]=1>>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[N:46]=[CH:47][C:48]([N:51]=[S:52]([CH3:57])([N:54]([CH3:55])[CH3:56])=[O:53])=[CH:49][N:50]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CN(C)S(C)(=O)=Nc1cnc(Cl)nc1
Product: CN(C)S(C)(=O)=Nc1cnc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)nc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N′-(2-chloropyrimidin-5-yl)-N,N-dimethyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.10 min; Mass spectrum (ESI+): m/z=702 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[N:12][C:11]2[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9](=[O:23])[N:8]3[N:24]=[CH:25][N:26]=[C:7]3[C:6]=2[CH:5]=1)(=[O:3])C.C1COCC1.C[Si](C)(C)[C:34]([F:37])([F:36])[F:35].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(=O)(O)[O-].[Na+]>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:10]2[C:11]3[N:12]=[CH:13][C:4]([CH:1]([OH:3])[C:34]([F:37])([F:36])[F:35])=[CH:5][C:6]=3[C:7]3=[N:26][CH:25]=[N:24][N:8]3[C:9]2=[O:23])=[CH:20][CH:19]=1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(C)=O)cnc32)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(O)C(F)(F)F)cnc32)cc1
Reaction time: 0.17 h
Yield: 48 %

Procedure:
9-Acetyl-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 81, 254 mg, 0.76 mmol), THF (1.3 mL) and 2 M trimethyl(trifluoromethyl)silane in THF (0.45 mL, 0.91 mmol) were combined and stirred for 10 minutes. A 2 M solution of tetrabutylammonium fluoride in THF (75 μl, 0.08 mmol) was added and stirring was continued for 3 days. Additional trimethyl(trifluoromethyl)silane (0.45 mL, 0.91 mmol) and tetrabutylammonium fluoride (75 μl, 0.08 mmol) was added and the mixture was stirred for 4 h. The reaction mixture was diluted with aqueous sodium bicarbonate (5 mL) and extracted with EtOAc (2×10 mL). The combined extracts were concentrated under vacuum. Purification (FCC, SiO2, 10 to 100%, EtOAc/hexanes) afforded the title compound (154 mg, 48%) as a white powder. 1H NMR (400 MHz, CDCl3+DMSO-d6) δ 3.27 (s, 3H), 4.80 (q, J=6.90 Hz, 1H), 5.24 (s, 2H), 6.33 (d, J=8.66 Hz, 2H), 7.05 (d, J=8.53 Hz, 2H), 7.91 (s, 1H), 8.32 (s, 1H), 8.39 (s, 1H). [M+H]=406.1.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=O.[C:24]([NH:27][N:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[NH:26])[NH2:25]>C(O)C>[NH2:26][C:24]1[N:27]([N:28]=[CH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[N:25]=1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Reactant: N=C(N)NN=Cc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(-c2ccc(-c3ccccc3)cc2)cn1N=Cc1ccccc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
7 ml (0.0507 mol) of triethylamine and 13.75 g (0.050 mol) of 2-bromo-4'-phenylaceto-phenone (Aldrich, Buchs, Switzerland; tech., Cat. no. 10,108-7) are added to a solution of 8.11 g (0.05 mol) of benzaldehyde guanylhydrazone in 40 ml of ethanol. The reaction mixture is stirred at 20° C. for 15 hours and is filtered, and the crystallizate is taken up in methylene chloride and acidified to pH 1 with 1N hydrochloric acid. After filtration, the filtration product is taken up in methanol, and 2N sodium hydroxide solution is added until a basic reaction is obtained (pH 11). Filtration is carried out and the crystalline product is washed with methanol/water (1:1). The title compound so obtained melts at 254°-255° C. (decomp.), 1H-NMR (DMSO): δ=8.60 (s, 1H); 8.10 (s, 1H); 7.93-7.98 (m, 2H); 7.67-7.83 (m, 6H); 7.32-7.55 (m, 6H); 6.24 (s, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:15]2[CH3:18])=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=1)C1C=CC=CC=1>[Pd].O1CCCC1>[OH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:15]2[CH3:18])=[C:11]([C:24]([F:27])([F:25])[F:26])[CH:10]=1
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)cc(OCc3ccccc3)cc2n1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(C(F)(F)F)cc(O)cc2n1C

Procedure:
The reaction was carried out in a manner similar to Reference Example 15 a) except for using 2.23 g (5.91 mmol) of ethyl 6-benzyloxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate, 0.3 g of 10% palladium/carbon and 50 ml of tetrahydrofuran. Ethyl 6-hydroxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate was thus obtained in an amount of 1.70 g.