Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:3]#[C:4][C:5]([CH3:18])([NH:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:6].C([Mg]Br)C.Cl[C:31]([O:33][CH3:34])=[O:32].O>C1COCC1>[CH3:34][O:33][C:31]([O:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:3]#[C:4][C:5]([CH3:6])([NH:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:18])=[O:32]
Reactant: COC(=O)Cl
Reactant: CCCCCCCC(O)C#CC(C)(C)NS(=O)(=O)c1ccc(C)cc1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCC(C#CC(C)(C)NS(=O)(=O)c1ccc(C)cc1)OC(=O)OC
Reaction time: 0.67 h
Yield: 86 %

Procedure:
In 10 ml of THF was dissolved 1.37 g (3.76 mmole) of the 5-hydroxy-2-methyl-2-tosylamino-3-dodecyne obtained in Reference Example 1, and a THF solution of ethylmagnesium bromide (8.27 mmole) was added thereto, followed by stirring for 40 minutes. To the mixture was added dropwise 0.668 ml (8.65 mmole) of methyl chloroformate, and stirring was further continued for 50 minutes. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed successively with a hydrochloric acid aqueous solution, a sodium hydrogencarbonate aqueous solution, and water, and then dried. The solvent was removed by distillation, and the residual oily substance was purified by column chromatography to obtain 1.37 g (percent yield: 86%) of 5-methoxycarbonyloxy-2-methyl-2-tosylamino-3-dodecyne.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]3[O:35][N:34]=[C:33]([CH:36]([CH3:38])[CH3:37])[N:32]=3)[CH2:27][CH2:26]2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28]([C:31]5[O:35][N:34]=[C:33]([CH:36]([CH3:38])[CH3:37])[N:32]=5)[CH2:27][CH2:26]4)=[CH:21][CH:22]=3)=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1ccc(B(O)O)cc1
Reactant: CC(C)c1noc(N2CCC(COc3ccc(Br)cc3)CC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(C(=O)NC5CC5)cc4)cc3)CC2)n1
Yield: 9.8 %

Procedure:
The title compound (9 mg, 5%) was prepared as a white solid from {4-[(cyclopropylamino)carbonyl]phenyl}boronic acid (41 mg, 0.2 mmol), 4-{[(4-bromophenyl)oxy]methyl}-1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidine (prepared as in Example 24, Step 1, 76 mg, 0.2 mmol), Pd(PPh3)2Cl2 (50 mg, 0.07 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, 2H, J=8.6 Hz), 7.59 (d, 2H, J=8.6 Hz), 7.54 (d, 2 H, J=8.8 Hz), 6.96 (d, 2H, J=8.8 Hz), 6.26 (s, 1H), 4.28-4.18 (m, 2H), 3.88 (d, 2H, J=6.2 Hz), 3.17-3.07 (m, 2H), 2.98-2.84 (m, 2H), 2.13-2.02 (m, 1H), 2.05-1.92 (m, 2H), 1.55-1.40 (m, 2H), 1.29 (d, 6H, J=6.9 Hz), 0.94-0.84 (m, 2H), 0.67-0.60 (m, 2H); LRMS (ESI), m/z 461 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1.[CH:12]([S:14]([CH:17]=[CH2:18])(=[O:16])=[O:15])=[CH2:13].[F:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:21]=1[NH2:22]>C(OCC)(=O)C>[F:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:21]=1[N:22]1[CH2:18][CH2:17][S:14](=[O:16])(=[O:15])[CH2:12][CH2:13]1
Reactant: C=CS(=O)(=O)C=C
Reactant: Nc1c(F)cccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: O=S1(=O)CCN(c2c(F)cccc2F)CC1
Temperature: 110 °C
Yield: 55.2 %

Procedure:
Aluminum chloride (310 g, 2.3 mol) is added to chlorobenzene (2.5 L) to give a cloudy green suspension. Vinyl sulfone (230 mL, 2.3 mol) is added via a funnel. 2,6-Difluoroaniline (250 mL, 2.3 mol) is added a via funnel. The light brown solution is heated to 110° C. Upon completion, the heat is removed and the black solution is self-cooled to 70° C. The reaction mixture is quenched in methylene chloride (4 L) and ice water (5 L). The aqueous phase is extracted with methylene chloride. The combined organic layers are concentrated and added branched octane (3 L), and then cooled to 0° C. for 30 minutes. The solids are filtered and washed with branched octane (2×500 mL). The crude black solids are dissolved into methylene chloride (3 L) and then loaded onto a SiO2 plug (1.8 kg). The column is eluted with dichloromethane (16 L) until clear. The methylene chloride solution is concentrated to give light brown solids (387 g or 68% yield). The solids are dissolved in hot ethyl acetate (3 L) followed by the addition of hexanes (900 mL). The black solution is self-cooled to room temperature overnight. The light amber crystal needles are filtered and washed with hexanes (4×250 mL). The solids are dried in vacuo at 50° C. overnight to give 314 g of the title compound (55% recystallized yield 1st crop).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[CH:12](=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15]>>[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[O:5][CH2:4][CH2:3][CH2:2][O:15][C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[CH:12]=[O:20]
Reactant: BrCCCOC1CCCCO1
Reactant: O=Cc1ccccc1O
Product: O=Cc1ccccc1OCCCOC1CCCCO1

Procedure:
By using 2-(3-bromopropoxy)tetrahydro-2H-pyran and salicylaldehyde, the title compound was obtained as colorless oil by similar procedures to those of Example 60b (yield: quantitative).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.Cl>C(O)C>[CH2:19]([N:16]([CH2:17][CH3:18])[CH2:15][CH2:14][S:11]([C:8]1[CH:7]=[CH:6][C:5]([NH2:4])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[CH3:20]
Reactant: CCN(CC)CCS(=O)(=O)c1ccc(NC(C)=O)cc1
Agent: Cl
Solvent: CCO
Product: CCN(CC)CCS(=O)(=O)c1ccc(N)cc1
Reaction time: 1 h

Procedure:
9.85 g of N-acetyl-4-(2-diethylamino-ethyl-sulphonyl)-aniline (educt XVII) are dissolved in 25 ml of ethanol and 100 ml of 3N hydrochloric acid are added. The mixture is stirred for 1 hour at reflux temperature. After cooling it is neutralised, extracted three times with methylene chloride, dried over magnesium sulphate and finally the solvent is eliminated.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1.O.[NH2:19][NH2:20]>N1C=CC=CC=1>[NH:19]([C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1)[NH2:20]
Reactant: FC(F)(F)c1cccc(-c2cnc(Cl)nn2)c1
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: NNc1ncc(-c2cccc(C(F)(F)F)c2)nn1
Temperature: 60 °C

Procedure:
A solution of 5.1 g. of 3-chloro-6-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazine in 30 ml. of pyridine is cooled to 0° C. and 3.5 ml. of hydrazine hydrate is added. The mixture is heated to 60° C., maintained at 60° C. for one hour, cooled and poured into ice-water. The resulting slurry is filtered and the solid is washed with ethanol giving 3-hydrazino-6-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazine as a yellow solid.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.[C:27](=[O:29])=[O:28]>O1CCCC1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][C:22]=1[C:27]([OH:29])=[O:28]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(F)(F)F)ccc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of n-BuLi (26.7 mL of 2.5M solution in tetrahydrofuran (THF), 66.7 mmol) in THF (130 mL) at −78° C. was added 2,2,6,6-tetramethylpiperidine (22.5 mL, 133.4 mmol). The mixture was stirred at −78° C. for 30 minutes and then carefully lowered to −100° C. using liquid nitrogen. Neat 1-bromo-4-(trifluoromethyl)benzene (15 g, 66.7 mmol) was added. The mixture was kept at −100° C. for 6 hours and poured onto freshly crushed dry ice. The resulting mixture was stirred at room temperature for 16 hours. The residue solvent was removed by evaporation. Water (150 mL) was added and the mixture was extracted with diethyl ether (3×50 mL). The aqueous layer was acidified using concentrated hydrochloric acid (HCl), extracted with methylene chloride (3×50 mL). The combined organic layers were washed with saturated sodium chloride (NaCl) (75 ml), dried with magnesium sulfate (MgSO4), filtered and concentrated to yield the title compound as a white solid (5.41 g). 1H NMR (400 MHz, CDCl3) δ 7.7 (dd, J=8.4, 2.3 Hz, 1 H) 7.9 (d, J=8.4 Hz, 1 H) 8.3 (d, J=2.0 Hz, 1 H). MS (ES+) Calc: 267.93, Found: 266.7 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][N:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])=[N:12][CH:13]=2)=[CH:24][CH:23]=1
Reactant: [H][H]
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(/C=C/c2ccc(F)cc2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(CCc2ccc(F)cc2)cn1
Reaction time: 240 h
Yield: 17.2 %

Procedure:
2-[(4-Fluorophenyl)sulfonyl]-5-[(E)-2-(4-fluorophenyl)vinyl]pyridine (Example 37, 0.11 g, 0.308 mmol) and palladium (10% wt. on activated carbon, 32 mg) were suspended in ethyl acetate (5 mL) and acetic acid (5 mL) and shaken in a Parr apparatus at 50 psi hydrogen for 2 days. The catalyst was removed by filtration, fresh catalyst (80 mg) added and shaking at 50 psi hydrogen continued for 10 days. The catalyst was removed by filtration and the solvent removed in vacuo. The residue was partitioned between saturated sodium carbonate solution and ethyl acetate. The aqueous phase was extracted with further portions of ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by mass-triggered preparative HPLC (Nebula) to give the title compound as a beige solid (19 mg, 17%). δH (500 MHz, d6 DMSO): 8.52 (1H, s), 8.10 (1H, d, J=8.0 Hz), 8.02–7.99 (2H, m), 7.95 (1H, dd, J=1.9, 8.0 Hz), 7.46 (2H, t, J=8.8 Hz), 7.21 (2H, dd, J=5.7, 8.4 Hz), 7.05 (2H, t, J=8.9 Hz), 2.97–2.94 (2H, m), 2.89–2.85 (2H, m); m/z (ES+) 360 [MH+].
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C1COCC1>[Pd].CO>[C:22]([O:21][C:19](=[O:20])[NH:18][CH2:17][CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CCNCC1
Reaction time: 48 h

Procedure:
A mixture of 28 g of 4-(tert-butoxycarbonylamino-methyl)-piperidine-1-carboxylic acid benzyl ester, 1 g of 10% palladium on carbon, 100 mL of THF and 200 mL of methanol was stirred under an atmosphere of hydrogen for 2 days. The mixture was filtered concentrated under reduced pressure. Drying under reduced pressure gave a white solid:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][Si](C(C)(C)C)(C)C)=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([OH:34])=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O[Si](C)(C)C(C)(C)C)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Yield: 76.8 %

Procedure:
A solution of 13.4 g of 5-benzyloxy-3-[1-tert-butoxycarbonyl-5-(tert-butyl-dimethylsilanyloxy)-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester and 6.15 g of tetrabutylammonium fluoride in 140 ml of anhydrous tetrahydrofuran is stirred at ambient temperature for 30 minutes. The solvent is evaporated off under vacuum. The reaction crude is taken up with 50 ml of dichloromethane and the organic phase is washed with 2 times 25 ml of distilled water. The organic phase is dried over magnesium sulfate. After filtration and concentration under vacuum, the reaction crude is purified by flash chromatography on 450 g of 40-63 μm silica. Elution is carried out with 100% dichloromethane and then a 98/2 then 95/5 dichloromethane/methanol mixture to Obtain 8.54 g of 5-benzyloxy-3-(1-tert-butoxycarbonyl-5-hydroxy-1H-indol-2-yl)indazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:10]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:8]([C:7]1[C:2]([C:17]2[CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=[CH:15][CH:16]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)#[N:9]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: N#Cc1cccnc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: N#Cc1cccnc1-c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 26.1 %

Procedure:
To a suspension of 2-chloro-3-cyanopyridine (0.693 g), 3-nitrophenylboronic acid (1.09 g) and tetrakis(triphenylphosphine)-palladium (289 mg) in 1,2-dimethoxyethane (20 ml) was added 2M aqueous solution of sodium carbonate (6.5 ml). The mixture was stirred at 80° C. for 24 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from 2-propanol. The precipitate was collected by filtration, washed with diisopropyl ether and dried to give 3-(3-cyanopyridin-2-yl)nitrobenzene (294 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[CH3:27][O:26][C:24](=[O:25])[CH2:23][N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)(=[O:11])=[O:10]
Reactant: COc1cccc(S(=O)(=O)Nc2ccc(Cl)cc2)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN(c1ccc(Cl)cc1)S(=O)(=O)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(4-chlorophenyl)-3-methoxy-benzenesulfonamide (900 mg, 3.02 mmol) in anhydrous THF (40 mL) was added sodium hydride (146 mg, 3.62 mmol) at 0-5° C. under nitrogen. The mixture was stirred at 25° C. for 30 minutes. Methyl bromoacetate (463 mg, 3.02 mmol) was then added, stirred for 1 h at 25° C. A further amount of methyl bromoacetate (232 mg, 1.51 mmol) was added, and stirring continued for another 12 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate (3×20 ml). The combined organic layer was washed with water, dried (Na2SO4), evaporated under reduced pressure to yield the title compound as oily compound, which was used as such in the next step. Yield: 1.03 g (92%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[F:11].[CH2:12]([B-](F)(F)F)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[K+].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:12]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[F:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Reactant: F[B-](F)(F)Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(Cc2ccccc2)c1F
Temperature: 100 °C
Yield: 62.5 %

Procedure:
To a mixture 1-bromo-2-fluoro-3-nitrobenzene (800 mg, 3.6 mmol), potassium benzyltrifluoroborate (2.2 g, 10.9 mmol) and Cs2CO3 (3.6 g, 10.9 mmol) in dioxane/H2O (10:1, 18 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (60 mg, 2 mol %) and the mixture was heated to 100° C. for 8 h. The mixture was cooled to RT, diluted with H2O and extracted with EtOAc. The combined extracts were washed with H2O, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (520 mg, 62%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:29])[NH:8][C:9]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[CH:14][C:13]=1[O:26][CH3:27])([O-])=O>C(O)(=O)C.[Pd]>[CH3:27][O:26][C:13]1[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=1[C:11]1[N:10]=[C:9]2[NH:8][C:7](=[O:29])[CH2:6][CH:5]=[C:4]2[N:1]=1
Reactant: COc1cc(OCc2ccccc2)ccc1C(=O)Nc1[nH]c(=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(O)ccc1C1=NC2=CCC(=O)NC2=N1
Temperature: 100 °C
Reaction time: 1.3 h

Procedure:
3.95 g of 5-nitro-6-(2-methoxy-4-benzyloxy-benzoylamino)-2-pyridone were hydrogenated in 350 ml of glacial acetic acid after the addition of 1 g of 10% palladium-on-charcoal for 1.7 hours at 80° C. under a pressure of 5 bar. The reaction mixture was then stirred at 100° C. for 1.3 hours. The catalyst was filtered off, and the filtrate was allowed to cool. The product which precipitated was washed with ether. By evaporating the filtrate and adding ether, further fractions were obtained. Yield: 2.3 g (60% of theory). Melting point: over 270° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:37][O:38][CH3:39])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.[OH-].[Na+]>O1CCCC1.CO>[CH3:39][O:38][CH2:37][CH:4]([CH2:3][O:2][CH3:1])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC(COC)COC)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Ethyl [2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (390 mg) was dissolved in a mixture of tetrahydrofuran (5 mL) and methanol (5 mL). To the mixture was added 1M aqueous sodium hydroxide solution (2 mL) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and 1M hydrochloric acid (2 mL) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (370 mg, 100%) as a pale orange amorphous solid. MS 550 (MH+).
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[O:22][N:21]=[C:20]([CH2:23][CH:24](OC)[O:25]C)[C:19]=2[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])=[O:30])[N:9]=[N:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[F:45][C:2]([F:1])([F:46])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([C:18]2[O:22][N:21]=[C:20]([CH2:23][CH:24]=[O:25])[C:19]=2[C:29](=[O:30])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[N:9]=[N:8]1
Reactant: COC(Cc1noc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=CCc1noc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Combine [5-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2,2-dimethoxy-ethyl)-isoxazol-4-yl]-(2-chloro-phenyl)-methanone (1 eq) in acetone/H2O (4:1) and p-toluenesulfonic acid (1 eq) with stirring. Attach a reflux condensor and stir overnight in a 60° C. oil bath. Neutralize with saturated aqueous NaHCO3, extract with ethyl acetate, dry over MgSO4, filter, and concentrate under vacuum. 1H NMR (CDCl3): δ 9.84 (s, 1H), 7.83 (s, 1H), 7.56–7.09 (m, 11H), 5.43 (s, 2H), 4.09 (s, 2H).
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1.[F:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[C:19]([C:28](O)=[O:29])=[N:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:15]([O:33][CH3:34])[CH:14]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C=O)C.CO>[F:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[C:19]([C:28]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:11])=[N:5][CH:6]=3)=[O:29])=[N:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:15]([O:33][CH3:34])[CH:14]=1
Reactant: COC(=O)c1ccc(N)cn1
Reactant: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CO
Product: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)Nc1ccc(C(=O)O)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
A solution of the 5-aminopicolinic acid methyl ester (15.2 mg, 0.1 mmol), 3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid (34.57 mg, 0.11 mmol), N-methylmorpholine (21.99 μL, 0.2 mmol) and HATU (45.6 mg, 0.12 mmol) in DMF (0.4 mL) was stirred at 40° C. for 16 hours. 3M aqueous NaOH solution (0.50 mmol, 166.7 μL) and methanol (0.2 mL) was added and the reaction mixture was stirred at 40° C. for 1 hour. The mixture was diluted with MeOH, filtered and purification by reverse phase HPLC using a gradient of 1-99% ACN in water and HCl as a modifier to yield 5-(3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)picolinic acid (32) (10.75 mg, 23%). ESI-MS m/z calc. 434.10, found 435.3 (M+1)+; Retention time: 1.33 minutes (3 minutes run). 1H NMR (400 MHz, DMSO) δ 13.12 (s br, 1H), 11.52 (s, 1H), 9.06 (d, J=2.3 Hz, 1H), 8.45 (dd, J=8.6, 2.5 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 8.14 (d, J=8.6 Hz, 1H), 7.82 (ddd, J=24.3, 15.6, 6.7 Hz, 3H), 7.36 (dd, J=8.8, 5.8 Hz, 1H), 7.16 (dd, J=10.6, 2.8 Hz, 1H), 6.88 (ddd, J=8.5, 2.8 Hz, 1H), 3.70 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[CH3:11])[C:5]([NH2:7])=[O:6].CO[C:15]([N:19]([CH3:21])[CH3:20])(OC)[CH3:16]>>[CH3:20][N:19]([CH3:21])/[C:15](=[N:7]/[C:5](=[O:6])[C:4]1[CH:8]=[C:9]([I:12])[C:10]([CH3:11])=[C:2]([F:1])[CH:3]=1)/[CH3:16]
Reactant: COC(C)(OC)N(C)C
Reactant: Cc1c(F)cc(C(N)=O)cc1I
Product: C/C(=N\C(=O)c1cc(F)c(C)c(I)c1)N(C)C
Temperature: 120 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of 3-fluoro-5-iodo-4-methylbenzamide (preparation 50b) and (1,1-dimethoxyethyl)dimethylamine was heated at 120° C. in a sealed tube. After 2 hours, the reaction mixture was cooled and the solvent was evaporated under reduced pressure to give the title compound (1.84 g, 100%) as an oil.