Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=2[CH3:30])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O)C.CC([O-])(C)C.[Na+]>C1COCC1>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:3])[N:22]([C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=3[CH3:30])[CH2:21][CH2:20][CH2:19]2)[CH2:7][CH2:8]1)=[O:13])([CH3:16])([CH3:18])[CH3:17]
Reactant: CCOC(=O)C1(CCCNc2ccc(Br)cc2C)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1N1CCCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[3-(4-Bromo-2-methyl-phenylamino)-propyl]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (3.78 g, 7.81 mmol, 1 eq) was dissolved in THF (80 mL). A 1M solution of NaOt-Bu in THF (7.8 mL, 7.8 mmol, 1 eq) was added and the reaction mixture was stirred for 2 h at rt. The reaction mixture was stirred for 48 h, quenched with 250 mL of water, transferred to a separatory funnel and extracted with dichloromethane (2×150 mL). The combined organics were dried over Na2SO4 and purified by column chromatography on silica gel (200 g column, 50% EtOAc in heptanes; 50 mL/min). This gave 2.49 g (73%) of the title compound as a beige gum.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH2:14][N:15]2[C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C:16]2=O)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Mg]I>>[NH:1]([C:8]1[N:13]=[C:12]([CH2:14][N:15]2[CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][C:20]2=[O:21])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCC(=O)N1Cc1ccnc(Nc2ccccc2)n1
Reactant: C[Mg]I
Product: CC1CCCC(=O)N1Cc1ccnc(Nc2ccccc2)n1

Procedure:
By an analogous process to Method 17, 2-anilino-4-(2,6-dioxopiperidin-1-ylmethyl)pyrimidine (Method 16; 2.21 g, 7.47 mmol) was treated with methyl magnesium iodide to prepare the intermediate animal which was taken on without chromatographic purification to give the final product which was purified, after aqueous work-up, by chromatography eluting with DCM/MeOH (98:2) to give the title compound (375 mg, 17%) as a glassy solid. NMR: 1.2 (d, 3H), 1.65 (m, 2H), 1.93 (m, 2H), 2.33 (t, 2H), 3.6 (q, 1H), 4.25 (d, 1H), 4.7 (d, 1H), 6.65 (d, 1H), 6.93 (t, 1H), 7.25 (t, 2H), 7.76 (d, 2H), 8.4 (d, 1H), 9.53 (s, 1H); m/z 297.
Reaction SMILES: C([O:14][NH:15][C:16]([CH:18]1[CH:24]([CH:25]([OH:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH:22]=[CH:21][CH2:20][N:19]1[S:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])=[O:17])(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[OH:14][NH:15][C:16]([CH:18]1[CH:24]([CH:25]([OH:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH:22]=[CH:21][CH2:20][N:19]1[S:33]([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)(=[O:35])=[O:34])=[O:17]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(C(O)c3ccccc3)C2C(=O)NOC(c2ccccc2)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CC=CCC(C(O)c3ccccc3)C2C(=O)NO)cc1
Temperature: 12.5 °C

Procedure:
A solution of 3-(hydroxy-phenyl-methyl)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid benzhydryloxy-amide (5 mg, 0.008 mmoL) in dichloromethane (1 mL) was cooled to 0° C. This solution was treated with trifluoroacetic acid (0.1 mL) followed by a 0.31 M solution of triethylsilane in dichloromethane (0.026 mL). The reaction mixture was warmed from 0 to 25° C. over 35 minutes and then the solvents were removed in vacuo and the residue was coevaporated with toluene. The residue was purified by flash chromatography (silica, 5 to 10% methanol in dichloromethane) to give 3-(hydroxy-phenyl-methyl)-1(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid hydroxyamide as a white solid; MS: (M-H)- 430.9.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH2:23][NH:24][C:25]2[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=2[CH3:33])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[Li][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1.O>CCOCC.ClCCl.CO.C(N(CC)CC)C.ClCCl.CO.ClCCl>[C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:24][C:25]2[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=2[CH3:33])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c(NCc2cccc(-c3c(CNC(C)(C)C)ccc4ccccc34)n2)c(C)c1
Reactant: [Li]c1ccccc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(NC(c2ccccc2)c2cccc(-c3c(CNC(C)(C)C)ccc4ccccc34)n2)c(C)c1
Temperature: -78 °C

Procedure:
To a solution of 1.56 g (3.60 mmol) of N-[(6-{2-[(tert-butylamino)methyl]-1-naphthyl}pyridin-2-yl)methyl]-2,4,6-trimethylaniline in 30 ml of THF 14.5 ml (10.7 mmol) of 0.74 M PhLi in ether was added by vigorous stirring at −78° C. The resulting mixture was heated to room temperature and then stirred for 10 min. Further on, 2 ml of water was added, and the resulting mixture was poured into 50 ml of water. The crude product was extracted with 3×30 ml of ether. The organic extract was washed with water, dried over K2CO3, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane, then dichloromethane-methanol 20/1 vol., then dichloromethane-methanol-triethylamine=100:10:1, vol.). Yield 1.66 g (90%) of orange oil. Anal. calc. for C36H39N3: C, 84.17; H, 7.65; N, 8.18. Found: C, 84.31; H, 7.77; N, 8.05. For 1H NMR (in CDCl3) see FIG. 1—Top spectrum.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C)C=O>[N:18]([CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1cccc2c1cnn2C1CCCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1cccc2c1cnn2C1CCCCO1
Temperature: 90 °C
Yield: 94.9 %

Procedure:
A mixture of 4-bromomethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (150 mg, 0.508 mmol) and sodium azide (132 mg, 2.0 mmol) in N,N-dimethylformamide (1.5 mL) was heated in a 90° C.-oil-bath for 30 min, then allowed to cool, and poured into water (5 mL). The mixture was extracted with ether (2×10 mL), dried (MgSO4), filtered, evaporated, and dried under high vacuum overnight to give 4-azidomethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (124 mg, 95%) as a yellow oil.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](I)[CH:11]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([SH:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>CN1CCCC1=O.C(N(CC)CC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:22][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:11]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: SC1CCCC1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(I)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cccc(SC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
Tert-butyl[(3-iodobenzyl)oxy]dimethylsilane (WO9513095) (1.44 g) in dry 1-methyl-2-pyrrolidone (15 ml) and triethylamine (4 ml) was stirred at room temperature under nitrogen. 1-1′Bis(diphenylphosphino)ferrocene (110 mg) and tris(dibenzylideneacetone)dipalladium(0) (258 mg) were added and the mixture was stirred for 15 min. Cyclopentyl mercaptan (0.42 g) was then added, and the reaction mixture stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature, poured onto water and extracted with diethyl ether. The combined organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The residue was purified on a 50 g SPE, eluting with a stepped gradient of 10 to 100% dichloromethane-cyclohexane to give the title compound (1.09 g) LCMS RT=4.67 min
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][N:14]1[C:22]2[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=[C:18]([NH2:25])[C:17]=2[N:16]=[C:15]1[CH3:26]>>[NH2:25][C:18]1[C:17]2[N:16]=[C:15]([CH3:26])[N:14]([CH2:13][CH2:12][O:11][CH2:10][CH2:9][NH:8][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[C:22]=2[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Reactant: CN(C)S(=O)(=O)Cl
Product: Cc1nc(N)c2nc(C)n(CCOCCNS(=O)(=O)N(C)C)c2c1C

Procedure:
Using the method of Examples 34–50, dimethylsulfamoyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5 -c]pyridin-4-amine to provide the desired compound. The product was purified using Method A. The observed accurate mass was 371.1861.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC.C1(C)C=CC=CC=1>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[C:19]([NH:18][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:20]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: FC(F)(F)c1ccc(-c2ccnc(Nc3cnc4ccccc4c3)c2)cc1
Temperature: 90 °C

Procedure:
To an oven-dried 50 mL round-bottomed flask were added 2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (138 mg, 0.54 mmol) and 3-aminoquinoline (Aldrich Chemical Company) (93 mg, 0.64 mmol), followed by anhydrous toluene (45 mL). Nitrogen was bubbled through the above solution via a needle for 1 h. Then palladium acetate (Aldrich Chemical Company) (18 mg, 0.08 mmol) and BINAP (Aldrich Chemical Company) (50 mg, 0.08 mmol) were added to the reaction in one portion, followed by sodium tert-butoxide (Aldrich Chemical Company) (145 mg, 1.5 mmol). The reaction mixture was heated at 90° C. overnight. After cooling to room temperature, the reaction mixture was taken up to ether, and washed with brine. The aqueous layer was extracted with ether (2×) and the combined ether layer was dried over Na2SO4 and concentrated. The residue was purified on a Biotage 40 S column (2.5:1 hexane:EtOAc) to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 366 (M+1). Mp: 207.4-207.5° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[N:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23](N(OC)C)=[O:24])=[N:15]1.[CH3:29][Mg+].[Br-]>C1COCC1>[C:23]([C:16]1[C:17](=[O:22])[C:18]([O:20][CH3:21])=[CH:19][N:14]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]3[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=3)[C:2]=2[F:1])[N:15]=1)(=[O:24])[CH3:29]
Reactant: C[Mg+]
Reactant: COc1cn(-c2cccc(-c3cnn(C)c3)c2F)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cccc(-c3cnn(C)c3)c2F)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 1.67 h
Yield: 79.8 %

Procedure:
To a solution of 1-[2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl]-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (345 mg, 0.890 mmol) in THF (100 mL) was added MeMgBr (1.0 M in THF, 2.67 mL, 2.67 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 100 min. The reaction was quenched with saturated NH4Cl aqueous solution at −78° C. The mixture was extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (EtOAc/MeOH=100/0 to 70/30) to yield the title compound (243 mg, 80% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.51 (3H, brs), 3.81 (3H, s), 3.91 (3H, s), 7.38-7.46 (1H, m), 7.54-7.64 (1H, m), 7.86-7.95 (1H, m, J=15.0, 1.7 Hz), 7.98 (1H, s), 8.25 (1H, d, J=2.3 Hz), 8.58 (1H, d, J=1.9 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][C:13]1[CH:14]=[C:15]([C:24]([O:26]CC)=[O:25])[C:16](=[O:23])[N:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)[CH2:6][CH2:5]2.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:23]=[C:16]1[N:17]2[C:22]([CH:21]=[CH:20][CH:19]=[CH:18]2)=[C:13]([CH2:12][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:3]=3)[CH2:8]2)[CH:14]=[C:15]1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1cc(CN2CCc3cc(Br)ccc3C2)c2ccccn2c1=O
Reactant: OB(O)c1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(CN2CCc3cc(-c4ccccc4)ccc3C2)c2ccccn2c1=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 1-[(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)methyl]-4-oxo-4H-quinolizine-3-carboxylate (0.045 g, 0.10 mmol), phenylboronic acid (0.019 g, 0.15 mmol), and 1 N cesium carbonate (0.20 mL, 0.20 mmol) in 1 mL THF under nitrogen was added bis (tri-tert-butyl-phosphine)palladium(0) (10 mol %). The reaction mixture was stirred at 100° C. for 3 hours, then cooled to rt and concentrated in vacuo. To a solution of the resultant brown residue in 1 mL DMSO was added saturated aqueous lithium hydroxide (0.3 mL). After 2 hours, the reaction was filtered and subjected to purification via reverse phase HPLC to provide the title compound which gave a mass ion (ES+) of 411.0. 1H NMR (400 MHz, DMSO) δ 10.2 (br s, 1H), 9.46 (d, J=6.2 Hz, 1H), 8.74 (s, 1H), 8.60-8.56 (m, 1H), 8.32-8.08 (m, 2H), 7.78-7.75 (m, 1H), 7.67-7.65 (m, 2H), 7.57-7.55 (m, 1H), 7.48-7.44 (m, 2H), 7.38 (d, J=7.4 Hz, 1H), 7.32-7.12 (m, 1H), 4.94 (s, 2H), 4.64-4.50 (m, 2H), 3.82-3.38 (m, 2H), 3.18-3.07 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[S:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]5[S:21][C:20]([NH:22][CH2:23][C:24]6[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=6)=[N:19][N:18]=5)[CH:15]=4)[N:10]([S:32]([C:35]4[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=4)(=[O:34])=[O:33])[CH:9]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:45][CH:44]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
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
Solvent: ClCCl
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(-c5ccc(Cl)cc5)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Temperature: 105 °C
Yield: 83.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(6-chloropyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (245 mg, 0.407 mmol) and 4-chlorophenylboronic acid (95 mg, 0.610 mmol) in p-dioxane/H2O (4:1, 4.5 mL) followed by potassium carbonate (168 mg, 1.221 mmol) and Pd(PPh3)4 (23.5 mg, 0.020 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 105° C. for 30 min. The mixture was diluted with DCM and washed with H2O and separated. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 0-20% EtOAc in DCM) to give 5-(3-(6-(4-chlorophenyl)pyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (230 mg, 0.339 mmol, 83%) as a light yellow solid. MS (ESI, pos. ion) m/z: 678 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.98 (1H, d, J=1.4 Hz), 8.15 (1H, s), 8.05-8.13 (3H, m), 7.98-8.03 (1H, m), 7.80-7.88 (3H, m), 7.66 (2H, d, J=8.2 Hz), 7.48 (2H, d, J=8.6 Hz), 7.33 (2H, d, J=8.6 Hz), 7.24 (2H, s), 6.89 (2H, d, J=8.6 Hz), 4.55 (2H, s), 3.80 (3H, s), 2.35 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:21][C:22]1[C:27]([Cl:28])=[CH:26][C:25]([NH:29][CH2:30][CH2:31][NH2:32])=[CH:24][C:23]=1[Cl:33]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:32][CH2:31][CH2:30][NH:29][C:25]3[CH:24]=[C:23]([Cl:33])[C:22]([NH2:21])=[C:27]([Cl:28])[CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: NCCNc1cc(Cl)c(N)c(Cl)c1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNCCNc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 2-(4-amino-3,5-dichlorophenylamino)-ethylamine analogously to Example 1.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH:7]([N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:12])[CH:8]([CH3:10])[CH3:9])(C)(C)C.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:11]([CH3:12])[C@H:7]([CH:8]([CH3:9])[CH3:10])[C:6]([OH:24])=[O:5])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COc1ccc(S(=O)(=O)N(C)C(C(=O)OC(C)(C)C)C(C)C)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@H](C(=O)O)N(C)S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
To a 0° solution of 0.707 g (1.980 mmol) of the product of Example 5 in 50 mL of dichloromethane was added 9.4 mL (9.395 mmol) of a 1.0M solution of boron tribromide in dichloromethane. The resulting mixture was stirred at 0° for 0.5 h and then warmed to room temperature and stirred for an additional 4 h. The reaction mixture was then poured into a saturated sodium bicarbonate solution and extracted with dichloromethane. The aqueous layer was acidified with 5% HCl solution and extracted with dichloromethane. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:1) to provide 0.271 g (48%) of the phenolcarboxylic acid as a colorless oil. Electrospray Mass Spec: 287.9 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[NH:6][N:5]=[C:4]1[C:10]1[CH:29]=[CH:28][C:13]2[N:14]=[C:15]([C:17]3[CH:27]=[CH:26][C:20]([O:21][CH:22]([CH3:25])[CH:23]=[O:24])=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1)[CH3:2].C(O)(=O)C.C(NC(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([CH:3]1[C:4]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:21][CH:22]([CH3:25])[CH2:23][OH:24])=[CH:26][CH:27]=4)[O:16][C:12]=3[CH:11]=2)=[N:5][NH:6][C:7](=[O:9])[CH2:8]1)[CH3:2]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OC(C)C=O)cc3)oc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OC(C)CO)cc3)oc2c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
40 mg (102 μmol) 2-{4-[6-(4-ethyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-benzoxazol-2-yl]-phenoxy}-propionaldehyde are placed in 2 mL DCM and 250 μL DMF. 6 μL (104 mmol) acetic acid and 22 μL (156 μmol) diisopropylamine are added and the mixture is stirred for 40 min at RT. Then 33 mg (156 μmol) sodium triacetoxyborohydride are added and the mixture is stirred for 3.5 h at RT. The reaction mixture is diluted with DCM and extracted successively with 10% sodium carbonate solution and sat. saline solution. The solv. of the organic phase is eliminated i.V. and the residue is purified through HPLC. (xBridge, MeOH/H2O+TFA) The corresponding fractions are freeze-dried.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)=[N:26][CH:27]=1>>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:29]4[CH:30]=[CH:31][N:32]=[C:28]4[C:25]4[CH:24]=[CH:23][C:22]([F:21])=[CH:27][N:26]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Fc1ccc(-c2ncc[nH]2)nc1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3ccc(F)cn3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 77, with Intermediate B instead of Intermediate C and with 5-fluoro-2-(1H-imidazol-2-yl)pyridine instead of 2-phenyl-1H-imidazole. LCMS: 422.3 m/z (M+H)+; ret. Time: 6.73 min (Analytical Method C).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[N:21]=[C:20]([CH3:22])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][CH:17]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:16]2[CH:17]=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 87.5 %

Procedure:
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (440 mg; 2.2 mmol), 6-chloro-2-methyl-3-nitro-pyridine (346 mg; 2.0 mmol), and triethylamine (420 μL; 3.0 mL) is dissolved in dimethylformamide (6 mL) and the resulting mixture is irradiated in a mono-mode microwave oven for 14 hours at 100° C. The reaction mixture is treated by aq. sat. ammonium chloride (5 mL), the precipitate formed is filtered, then rinsed with water (2 mL) and dried under high vacuum to afford the desired product (590 mg; 1.75 mmol).