Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[N:8][C:7]=2[CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+].Cl>CCCCCCC>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[N:8][C:7]=2[CH:15]=1
Reactant: COc1ccc2sc(S(N)(=O)=O)nc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Product: NS(=O)(=O)c1nc2cc(O)ccc2s1
Temperature: 0 °C
Yield: 58.8 %

Procedure:
A stirred suspension of 5-methoxy-2-benzothiazolesulfonamide (11.8 g, 0.048 mole) and aluminum chloride (28 g, 0.21 mole) in heptane (500 ml) was heated at reflux for 21/2 hours then cooled. The aluminum chloride complex was decomposed by the addition of ice water (400 ml) to give 6.5 g of 5-hydroxy-2-benzothiazolesulfonamide which melts at 224° C. after reprecipitiation from dilute sodium hydroxide with dilute hydrochloric acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([C:16]2[N:25]=[C:24]([NH:26][C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[N:32](C(OC(C)(C)C)=O)[N:31]=[CH:30]4)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH:13]=[CH:14][CH:15]=1)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:32]1[C:33]2[C:29](=[CH:28][C:27]([NH:26][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]([C:12]4[CH:11]=[C:10]([NH:9][C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[O:8])[CH:15]=[CH:14][CH:13]=4)[N:25]=3)=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: CN1CCC[C@H]1C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC[C@H]1C(=O)Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-((S)-1-methylpyrrolidine-2-carboxamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate (22 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35—90 mins) to afford (2S)—N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-1-methylpyrrolidine-2-carboxamide. (25 mg, 25%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N+:49]([C:52]1[CH:63]=[CH:62][C:55]2[NH:56][C:57]([C@@H:59]([NH2:61])[CH3:60])=[N:58][C:54]=2[CH:53]=1)([O-:51])=[O:50]>CN(C)C=O.ClCCl.C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([NH:61][C@H:59]([C:57]1[NH:56][C:55]2[CH:62]=[CH:63][C:52]([N+:49]([O-:51])=[O:50])=[CH:53][C:54]=2[N:58]=1)[CH3:60])=[O:7]
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: C[C@H](N)c1nc2cc([N+](=O)[O-])ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc([N+](=O)[O-])ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 87 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-nitro-1H-benzimidazol-2-yl)ethylamine in dimethylformamide. Yield: 87%; Rf value: 0.40 (silica gel; dichloromethane/ethanol=9:1); C22H23N5O4 (421.46); mass spectrum: (M+H)+=422 and (M−H)−=420
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)C(C)C)(C)C.[C:45]([C:47]1[CH:76]=[CH:75][C:50]([O:51][C:52]2[C:57]([C:58]([N:60]3[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)=[O:59])=[CH:56][CH:55]=[C:54]([O:66][C:67]3[CH:72]=[CH:71][C:70]([C:73]#[N:74])=[CH:69][CH:68]=3)[N:53]=2)=[CH:49][CH:48]=1)#[N:46]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]([N:63]1[CH2:64][CH2:65][N:60]([C:58]([C:57]2[C:52]([O:51][C:50]3[CH:49]=[CH:48][C:47]([C:45]#[N:46])=[CH:76][CH:75]=3)=[N:53][C:54]([O:66][C:67]3[CH:68]=[CH:69][C:70]([C:73]#[N:74])=[CH:71][CH:72]=3)=[CH:55][CH:56]=2)=[O:59])[CH2:61][CH2:62]1)=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(Oc2ccc(C(=O)N3CCNCC3)c(Oc3ccc(C#N)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCN(C(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 3-tert-butoxycarbonylamino-propionic acid, 0.177 g (0.94 mmol), in 3 ml of DMF was added dropwise to a stirred suspension of 0.72 g (3.76 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and hydroxybenzotriazole (HOBT) 0.508 g (3.76 mmol) in 5 ml of DMF at RT. That was followed by the addition of N,N-diisopropylethylamine (DIPEA) 0.242 g (1.88 mmol) while the temperature was maintained below 5. The mixture was stirred for 10 min and a solution of 4-[2,6-Bis-(4-cyano phenoxy)pyridine-3-carbonyl]piperazine (0.4 g, 0.94 mmol) in DMF (10 ml) was added followed by stirring overnight at RT. The reaction mixture was concentrated under reduced pressure and partitioned between water (150 ml) and ethyl acetate (150 ml) after the pH was adjusted to 2-3 with 6 N HCl. The organic phase was washed with 1 M Na2CO3 and saturated brine solution, dried over sodium sulphate and concentrated. The crude oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.45 g of the required product. Percentage purity (LCMS): 10.3%. (M+1)=596.2 (with BOC).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([OH:29])(=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\C/C=C\CCCCC.C([OH:39])CCCCCCCC>>[CH2:1]=[CH:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:39]=[CH:19]/[CH:18]=[CH:17]/[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([OH:29])=[O:28]
Reactant: CCCCCCCCCO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: C=CC(O)CCCCC
Product: O=C/C=C/CCCCCCC(=O)O

Procedure:
Three mushroom supernatants were made using the method similar to the procedure for 1-octen-3-ol analysis (Mau, (1992)). Mushroom supernatants were prepared by blending 50 g of mushrooms with 100 mL of 0.1M Na phosphate buffer, pH 6.5, and linoleic acid (0, 25.6 and 51.2 mg for supernatants A, B and C, respectively). 1-Nonanol was added as an internal standard prior to blending in order to quantify 1-octen-3-ol. After pentane extraction and centrifugation, the pentane layer was removed for 1-octen-3-ol assay, and the supernatant (ca 135 ml) was adjusted to the final volume of 200 mL using deionized H2O. Due to the fact that 1-octen-3-ol and 10-oxo-trans-8-decenoic acid are formed at the molar ratio of 1:1 (Wurzenberger et al., (1982)), the concentrations of ODA in supernatants were computed directly from the 1-octen-3-ol content to be 2.7×10-5, 4.8×10-4, and 9.4×10-4M for supernatants A, B and C, respectively.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.C([Li])(C)(C)C.[CH2:18]([S:20]SCC)[CH3:19]>C1COCC1>[CH2:18]([S:20][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)[CH3:19]
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CCSSCC
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCSc1ccc2cc[nH]c2c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
To a mixture of potassium hydride (30% wt. in mineral oil, 2.71 g, 20.2 mmol) and THF (30 mL) was added a solution of 6-bromoindole (3.98 g, 20.3 mmol) in THF (10 mL) at 0° C. After 15 minutes the solution was cooled to −78° C., and tert-butyllithium (1.5 M in pentane, 27.07 mL, 40.60 mmol) was added via syringe. The mixture was stirred at −78° C. for 10 min then ethyl disulfide (4.97 g, 40.6 mmol) in THF (10 mL) was added. The reaction mixture was allowed to warm to room temperature, poured into ice-sat.aq. NH4Cl (150 mL), and then extracted with EtOAc (150 mL). The organic phase was washed with water (150 mL), brine (150 mL), dried over Mg2SO4, concentrated, and purified on silica gel (EtOAc/hexane 5% to 15%), to provide 6-ethylsulfanyl-1H-indole (2.75 g, 77%) as a clear liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH2:8][C:7]1[C:14]3[C:19]([N:20]([CH3:21])[C:6]2=1)=[CH:18][CH:17]=[C:16]([O:22]C)[CH:15]=3.CN1C2C(=CC(O)=CC=2)C2N(C)C3C(C=2C1)=CC(O)=CC=3>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH2:8][C:7]1[C:14]3[C:19]([N:20]([CH3:21])[C:6]2=1)=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=3
Reactant: COc1ccc2c(c1)-c1c(c3cc(OC)ccc3n1C)CN2C
Agent: CN1Cc2c(n(C)c3ccc(O)cc23)-c2cc(O)ccc21
Product: COc1ccc2c(c1)-c1c(c3cc(O)ccc3n1C)CN2C

Procedure:
Following the procedure in Example 58, using 2,8-dimethoxy-5,11-dimethyl-5,11-dihydro-6H-indolo[3,2-c]quinoline (150 mg) as the starting material, 5,11-dimethyl-5,11-dihydro-6H-indolo[3,2-c]quinoline-2,8-diol as was obtained a brown solid and 2-methoxy-5,11-dimethyl-5,11-dihydro-6H-indolo[3,2-c]quinolin-8-ol was obtained as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH:8]([C:20]2O[C:22](CC)=[CH:23][CH:24]=2)[C:9]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[CH2:39][CH2:40]Cl>>[CH2:1]([C:3]1[O:7][C:6]2[C:8]3[C:9]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:10]=4[C:11](=[O:12])[NH:13][C:20]=3[CH2:24][CH:23]=[C:22]([CH2:39][CH3:40])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(c2ccc(CC)o2)c2ccc(OC)cc2C(N)=O)o1
Reactant: ClCCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCC1=CCc2[nH]c(=O)c3cc(OC)ccc3c2-c2oc(CC)cc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
Under argon, 2-formyl-5-methoxybenzoic acid (10 mmol) and 2-ethylfuran (40 mmol) were dissolved in abs. dioxane (20 ml), and after 10 minutes of stirring at room temperature, conc. perchloric acid (0.3 ml) was added. The resulting reaction mixture was subsequently stirred at 60° C. for 1 h, then poured into water and stirred. Filtration and drying of the resulting precipitate gave 2-[bis(5-ethyl-2-furyl)methyl]-5-methoxybenzoic acid in the form of a colourless solid (60% of theory). 2-[Bis(5-ethyl-2-furyl)methyl]-5-methoxybenzoic acid (10 mmol), dicyclohexylcarbodiimide (2.27 g, 11 mmol) were dissolved in abs. dichloromethane (90 ml) and stirred at room temperature for 10 min. Aqueous ammonia (4 ml) was then added, and the resulting reaction mixture was then stirred at room temperature for 1 h. Filtration, concentration under reduced pressure and subsequent purification by column chromatography (gradient ethyl acetate/n-heptane) of the residue that remained gave 2-[bis(5-ethyl-2-fury))methyl]-5-methoxybenzamide (982 mg, 28% of theory) in the form of a colourless solid. Under argon, abs. 1,2-dichloroethane (10 ml) was added to 2-[bis(5-ethyl-2-furyl)methyl]-5-methoxybenzamide (706 mg, 2 mmol) and p-toluenesulphonic acid bound to macroporous polystyrene resin (2 mmol). The resulting reaction mixture was stirred at a temperature of 100° C. for 1 h, after cooling to room temperature filtered off through Celite and concentrated under reduced pressure. Purification of the residue that remained by column chromatography (gradient ethyl acetate/n-heptane) gave 2,4-diethyl-10-methoxy-6,7-dihydro-8H-furo[2′,3′:3,4]cyclohepta[1,2-c]isoquinolin-8-one (51 mg, 8% of theory) in the form of a colourless solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 11.66 (br. s, 1H, NH), 8.31 (d, 1H), 7.68 (d, 1H), 7.38 (dd, 1H), 6.47 (s, 1H), 5.35 (t, 1H), 3.87 (s, 3H), 2.79 (q, 2H), 2.68 (m, 2H), 2.33 (q, 2H), 1.30 (t, 3H), 0.96 (t, 3H).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1)=[N+:13]=[N-:14]>>[ClH:1].[ClH:1].[NH:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[CH2:15][N:12]1[CH:5]=[C:4]([CH2:3][CH2:2][C:6]2[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=2)[N:14]=[N:13]1
Reactant: [N-]=[N+]=NCc1nc2ccccc2[nH]1
Reactant: C#CCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCc2cn(Cc3nc4ccccc4[nH]3)nn2)c[nH]1
Yield: 95.9 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.061 g, 0.361 mmol) was reacted with 2-azidomethyl-1-H-benzimidazole (0.075 g, 0.433 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(1H-Benzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine dihydrochloride (0.066 g, 48%) of a yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.05 (s, 1H), δ 7.68 (m, 2H), δ 7.48 (m, 2H), δ 6.38 (s, 1H), δ 6.15 (s, 2H), δ 2.90 (t, 2H), δ 2.76 (t, 2H) ppm; 13C (75 MHz, CD3OD) δ 147.4, 146.9, 146.8, 131.3, 127.0, 126.4, 124.1, 114.1, 109.2, 44.7, 24.0, 23.9 ppm; HRMS (ESI) calcd for C15H17N8 (M+) 309.1570. Found 309.1572.
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([O:13][C:14]1[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:6]([O:13][C:14]1[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:24]([C:26]1[CH:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:29]=[CH:30][CH:31]=1)=[CH2:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: CC(C)(C)c1cccc(C(=O)c2cccc(-c3ccccn3)c2)c1OCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(c1cccc(-c2ccccn2)c1)c1cccc(C(C)(C)C)c1OCc1ccccc1
Reaction time: 1 h
Yield: 91 %

Procedure:
Methyl triphenylphosphonium bromide (2.2 g, 6.17 mmol) was suspended in anhydrous tetrahydrofuran (20 mL) and stirred under nitrogen on an ice bath. 2.5M n-Butyllithium in hexanes (2.3 mL, 5.75 mmol) was added at such a rate that temperature did not exceed 3° C. Stirring was continued at room temperature for 1 hr. The reaction mixture was cooled on an ice bath and a solution of 4 (1.3 g, 3.08 mmol) in tetrahydrofuran (8 mL) was added at such a rate that temperature did not exceed 3° C. Stirring was continued at room temperature overnight. The reaction mixture was poured on saturated ammonium chloride (150 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×80 mL) and dried over sodium sulfate. The solvent was removed on a rotary evaporator and the crude product was purified by chromatography on silica (80 g) with 2% ethyl acetate in heptane (2 L), then 4% (4 L) to produce 5 (1.18 g, 91%).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([CH2:17][N:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19]2)[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C1C2CN(Cc3ccccc3)CC2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
N-Benzylmaleimide (5.0 g, 26.7 mmol), and N-(methoxymethyl)-N-(trimethylsilylmethyl) benzylamine (7.0 g, 29.4 mmol) were dissolved in toluene (150 mL). Trifluoroacetic acid (500 μL, 6.5 mmol) was added at room temperature. The reaction was allowed to stir for two hours at room temperature, and the precipitate was filtered off (˜440 mg). The filtrate was concentrated and purified by silica gel column chromatography (20-50% ethyl acetate in hexanes) to afford a white solid (6.2 g, 72%). 1H NMR (400 MHz, CDCl3): δ 7.22-7.05 (m, 8H), 7.01-6.96 (m, 2H), 4.45 (s, 2H), 3.95 (s, 2H), 3.50 (d, J=11.0 Hz), 3.37 (d, J=8.8 Hz), 3.10 (app t, J=9.1 Hz); 13C NMR (400 MHz, CDCl3): δ 175.8 (C═O), 134.8 (Ph), 130.6 (Ph), 129.6 (Ph), 129.3 (Ph), 128.8 (Ph), 128.6 (Ph), 128.3 (Ph), 127.7 (Ph), 57.3 (CH2), 54.0 (CH2), 42.9 (CH), 42.6 (CH2).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([CH3:11])[N:9]=[CH:10][C:3]=12.C[Si]([C:16]#[C:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:22][CH:23]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:11][N:8]1[C:4]2=[CH:5][N:6]=[CH:7][C:2]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:21]=[CH:22][CH:23]=3)=[C:3]2[CH:10]=[N:9]1
Reactant: C[Si](C)(C)C#Cc1cccc(NC(=O)c2ccccc2)c1
Reactant: Cn1ncc2c(Br)cncc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: Cn1ncc2c(C#Cc3cccc(NC(=O)c4ccccc4)c3)cncc21
Temperature: 80 °C

Procedure:
In an adaption of GP 3c, 60 mg of 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (Intermediate 2.1, 0.28 mmol, 1 eq), 140 mg N-(3-trimethylsilanylethynyl-phenyl)-benzamide (0.48 mmol, 1.68 eq.), 10 mg dichlorobis(triphenylphosphine)palladium (II) (PdCl2(PPh3)2) (0.014 mmol, 5 mol %) and 10.8 mg copper (I) iodide (0.057 mmol, 0.2 eq.) were dissolved in 1.4 mL THF (0.2 M) and treated with 0.35 mL tetra-n-butylammonium fluoride solution (1.0 M in THF, 0.35 mmol, 1.25 eq.). The resulting mixture was heated to 80° C. in a Biotage Initiator microwave oven for 30 min. Extractive work-up followed by column chromatography and preparative HPLC purification provided the target compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:35])[N:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:37]([NH2:42])(=[O:41])[CH:38]([CH3:40])[CH3:39].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[F:36][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1[C:20](=[O:35])[N:21]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH3:27])=[O:18]
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Reactant: CC(C)C(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(=O)C(C)C)c2)cc1F
Yield: 33.5 %

Procedure:
Using the procedure of Example 4, N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.15 g, 0.29 mmol), isobutyramide (0.10 g, 1.16 mmol), Xantphos (0.02 g, 0.032 mmol), and Cs2CO3 (0.14 g, 0.44 mmol), Pd2(dba)3 (0.015 g, 0.015 mmol), and dioxane (5 mL) were combined to obtain N-(2,5-difluoro-4-((2-isobutyramidopyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (55 mg, 35% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H), 10.52 (s, 1H), 8.34-8.33 (m, 1H), 8.19 (d, J=5.7 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.50-7.49 (m, 3H), 7.36 (t, J=8.7 Hz, 2H), 6.74 (dd, J=5.7, 2.5 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H), 4.28 (q, J=7.0 Hz, 2H), 2.69 (m, 1H), 1.34 (t, J=7.0 Hz, 3H), 1.02 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 581.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccncc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccncc2N)CC1
Yield: 95.9 %

Procedure:
1-methyl-4-(3-nitro-4-pyridyl)piperazine 14 (2.56 g, 11.52 mmol) in methanol (200 mL) was treated with palladium on carbon (10% wt % Degussa) (300 mg) and hydrogenated under balloon pressure at RT for 3 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 4-(4-methylpiperazin-1-yl)pyridin-3-amine 15 as a colourless solid (2.124 g, 11.05 mmol, 95.89%). MS (ES+) 193.1.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:35][C@H:36]([OH:64])[C:37]#[C:38][C@H:39]([CH3:63])[C@H:40]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[C@@H:41]([CH3:54])[CH2:42][C@@H:43]([CH3:53])[CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C@H:10]([CH3:34])/[CH:11]=[CH:12]/[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C1(C)C=CC=CC=1>[Si:1]([O:8][C@@H:9]([CH2:35][C@H:36]([OH:64])/[CH:37]=[CH:38]\[C@H:39]([CH3:63])[C@H:40]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[C@@H:41]([CH3:54])[CH2:42][C@@H:43]([CH3:53])[CH2:44][O:45][Si:46]([C:49]([CH3:50])([CH3:51])[CH3:52])([CH3:48])[CH3:47])[C@H:10]([CH3:34])/[CH:11]=[CH:12]/[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C#C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: Cc1ccccc1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 91.1 %

Procedure:
A catalytic amount of Lindlar catalyst (ca. 200 mg) was added to a solution of alcohol 33 (4.18 g, 4.51 mmol) in toluene (100 mL). The flask was flushed with H2 via a balloon several times, then stirred under an atmosphere of H2 until starting material was consumed (usually 1 h) as indicated by TLC analysis. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to afford the alkene 34 as a colorless oil (3.82 g, 91%): IR (CHCl3) 3436, 2954, 2926, 2855, 1461, 1378, 1252, 1061, 836, 773 cm−11; 1H NMR (300 MHz, CDCl3) δ 7.56 (m, 6H), 7.34 (m, 9H), 5.73 (m, 2H), 5.60 (t, J=10.3 Hz, 1H), 5.43 (dd, J=10.9, 8.4 Hz, 1H), 4.73 (m, 1H), 3.98 (q, J=5.0 Hz, 1H), 3.68 (d, J=4.1 Hz, 1H), 3.59 (dd, J=9.7, 4.7 Hz, 1H), 3.48 (m, 1H), 3.36 (dd, J=9.0, 7.3 Hz, 1H), 2.79 (m, 1H), 2.58 (m, 1H), 2.23 (br, 1H), 1.78 (m, 1H), 1.71 (m, 1H), 1.66 (m, 2H), 1.50 (m, 1H), 1.11 (d, J=6.8 Hz, 3H), 1.07 (d, J=6.8 Hz, 3H), 1.00 (m, 34H), 0.22 (s, 3H), 0.18 (s, 3H), 0.14 (s, 6H), 0.13 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 144.3, 135.3, 134.6, 131.5, 128.7, 127.7, 127.0, 126.8, 86.8, 79.6, 73.0, 68.2, 65.0, 64.7, 42.0, 39.6, 38.0, 36.4, 34.9, 33.4, 26.2, 26.0, 25.9, 19.9, 18.4, 18.3, 18.1, 18.0, 15.2, 14.5, −3.4, −3.7, −4.2, −4.4, −4.5, −5.4; LRMS (ESI) 951.7 [M+Na]+, 413.3, 243.1; HRMS (ESI) calcd for C56H92O5Si3Na 951.6150 [M+Na]+, found 951.6172; [α]20D 1.0 (c 0.62, CHCl3).