Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=[C:5]2[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]2[N:29]([S:45]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[C:30]([Sn](CCCC)(CCCC)CCCC)=[CH:31][C:24]=12.N#N>C1(C)C=CC=CC=1.[Cu]I.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:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]2[N:29]([S:45]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[C:30]([C:2]3[C:6]4=[N:7][C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=[C:5]4[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:3]=3)=[CH:31][C:24]=12
Reactant: COc1cc2c(nc1OC)c(Br)cn2C(=O)OC(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(Cl)ccnc2n1S(=O)(=O)c1ccc(C)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: Cc1ccccc1
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 68.6 %

Procedure:
Bubble a solution of dimethoxyazaindole 11 (0.25 g, 0.70 mmol) and azaindole 26 (0.458 g, 0.77 mmol) in toluene (15 mL) with N2 for 15 min, then add CuI (14 mg, 0.07 mmol) and Pd(PPh3)4 (81 mg, 0.07 mmol) and agitate the mixture with the stream of N2 for 0.5 h, then heat at 120° C. under N2 for 20 h. Purification of the reaction mixture on SiO2 (flash chromatography, 40 g cartridge, elution with EtOAc at 10-30%/heptane) gives bisazaindole 27 (0.28 g, 68%) as a white solid: 1H NMR (CDCl3) δ 8.29 (d, 1H, J=5.4 Hz), 7.86 (s apparent overlapping d, 3H), 7.15 (m, 4H), 6.94 (s, 1H), 3.97 (s, 6H), 2.32 (s, 3H), 1.71 (s, 9H), TLC (EtOAc at 40%/heptane) Rf=0.40.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:5]=[N:6][CH:7]=1.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1B(O)O>>[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cncc(Br)c1
Reactant: Cn1c(B(O)O)cc2ccccc21
Product: Cn1c(-c2cncc(CN3C(=O)c4ccccc4C3=O)c2)cc2ccccc21

Procedure:
2-(5-Bromo-pyridin-3-ylmethyl)-isoindole-1,3-dione (Example 186b) and 1-methyl-indole-2-boronic acid are processed according to the method described in Example 100 to give 2-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-isoindole-1,3-dione as a solid. MS (ESI) m/z 368.09 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[OH:11].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[K]>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)c1cc(I)ccc1O
Agent: [K]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(I)cc1C(=O)OC
Yield: 96.1 %

Procedure:
Reflux a mixture of 2-hydroxy-5-iodo-benzoic acid methyl ester (TCI; 5.5 g, 20 mmol) and ethyl bromoacetate (Aldrich; 6.7 g, 40 mmol) in acetone (60 mL) in the presence of potassium (5.5 g, 40 mmol) for 3 h. Filter out the solid and evaporate acetone to give a white residue. Dissolve the residue in ethyl acetate and wash with brine. Evaporate the solvent in vacuum to give final product as a white solid (7 g, 96%). MS (electrospray, m/z) 365 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.1 (d, J=2.0 Hz, 1H), 7.70 (dd, J=8.8, 2.8 Hz, 1H), 6.6 (d, J=8.8 Hz, 1H), 4.68 (s, 2H), 4.3 (q, J=6.8 Hz, 2H), 3.9 (s, 1H), 1.3 (t, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[OH:13].CCN=C=NCCCN(C)C.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>O>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:10])[F:11])=[CH:4][C:3]([OH:13])=[C:2]([NH:1][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:7]=1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1O
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cl)c(C(F)(F)F)cc1O)c1ccncc1
Temperature: 80 °C
Yield: 53.8 %

Procedure:
A mixture of 0.70 g of 2-amino-4-chloro-5-trifluoromethylphenol, 0.79 g of WSC, 0.39 g of isonicotinic acid and 6 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.54 g of N-[5-chloro-2-hydroxy-4-trifluoromethylphenyl]isonicotinamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:6][CH:7]=1.Cl.O([NH2:20])C>C(O)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH2:20])[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CON
Reactant: O=C(Cc1cccc(F)c1)c1cccnc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: NC(Cc1cccc(F)c1)c1cccnc1
Reaction time: 14 h

Procedure:
The intermediate oxime was prepared from 2-(3-fluoro-phenyl)-1-pyridin-3-yl-ethanone (crude) and methoxylamine hydrochloride (6.50 g, 77.83 mmol) according to the protocol described in general procedure B. The oxime was then dissolved in acetic acid (10.00 mL) and Pd/C (0.80 g) was added. The reaction mixture was hydrogenated under 50 psi for 14 hours, then filtered and concentrated. The residue was basified with 5M sodium hydroxide and extracted with methylene chloride. The combined organic phases were dried over potassium carbonate and concentrated to yield the title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.83 ((dd, J=7.04, 3.22 Hz, 2 H) 4.07 (t, J=7.04 Hz, 1 H) 6.96-7.08 (m, 2 H) 7.11 (td, J=5.86, 2.64 Hz, 1 H) 7.14-7.23 (m, 1 H) 7.27 (dd, J=7.48, 5.13 Hz, 1 H) 7.70 (ddd, J=7.77, 2.20, 2.05 Hz, 1 H) 8.36 (dd, J=4.84, 1.61 Hz, 1 H) 8.41 (t, J=3.08 Hz, 1 H).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br.Cl[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([NH2:19])=[N:17][N:18]=2)[N:15]=1.O>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([NH2:19])=[N:17][N:18]=3)[N:15]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: Nc1nnc2ccc(Cl)nn12
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nnc2ccc(OCC3CC3)nn12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Cyclopropylmethanol (2.64 ml) was initially charged in DMF (35 ml), admixed under argon with sodium hydride (795 mg) and stirred at 40° C. for 1 h. Subsequently, 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001; 1.66 g), dissolved in DMF (35 ml), were added dropwise. After 1 h, the mixture was admixed with water and extracted by shaking four times with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated by rotary evaporation. The residue was triturated with MtB ether, filtered off with suction and dried. 720 mg of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11](OCC)[CH3:12]>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:11]([C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:12]
Reactant: BrC1=Cc2ccccc2C1
Reactant: CCOCC
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Product: CCC1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Bromoindene (8.1235 g, 0.04211 moles) and Ni(dppp)Cl2 (0.1536 g, 2.83×10-4 moles) were stirred in diethylether (100 mL) at -78° C. under a nitrogen atmosphere as ethylMgBr (0.045 moles, 15.00 mL of 3.0 M solution in diethylether) was added. The dry-ice bath was then removed and the reaction mixture allowed to warm to room temperature. The reaction mixture started off as a heterogeneous brick-red color and then turned to a homogeneous yellow/gold solution and then back to the heterogeneous brick-red mixture during the course of the warm-up. Gas chromatographic analysis after 2 hours of stirring at room temperature showed that the reaction was substantially quantitative. After the reaction period the mixture was poured onto ice and then extracted with 1 M HCL (1×100 mL) and 1 M NaHCO3 (1×100 mL) and then dried with MgSO4 and filtered. The desired product was isolated as a light yellow oil (5.65 g, 93.1 percent).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:5]([CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)=[O:6].[C:22]([Mg]Cl)([CH3:25])([CH3:24])[CH3:23].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:5]([CH:7]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:8]2)([OH:6])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)c2cc(F)cc(F)c2)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(O)(c2cc(F)cc(F)c2)C(C)(C)C)C1
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
To a solution of 3.07 g (10.34 mmol) of tert-butyl 3-(3,5-difluorobenzoyl)azetidine-1-carboxylate in 20 mL of THF, 36.19 mL (36.19 mmol) of tert-butyl magnesium chloride was added and stirred for 3.5 h at −78° C. To the solution was added 8 mL of aq. NH4Cl and the solution was filtered to remove the solid. The filtrate was washed with ether. The combined organic layer was concentrated to remove solvents and residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound; 1H-NMR (CDCl3) δ 0.897 (s, 9H), 1.425 (s, 9H), 2.234 (br, 1H), 3.25 (m, 1H), 3.55 (m, 1H), 3.71 (t, J=8.9 Hz, 1H), 3.97 (t, J=8.4 Hz, 1H), 4.17 (m, 1H), 6.53-6.74 (m, 3H).
Reaction SMILES: ClC1C=C(C2ON=C(C3C=CC4OC(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)=CC=4C=3)N=2)C=CC=1OCCC.CC1(C)[O:48][CH2:47][C:46]([NH:66]C(=O)OC(C)(C)C)([C:49]2[S:53][C:52]3[CH:54]=[CH:55][C:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])=[CH:57][C:51]=3[CH:50]=2)[CH2:45][O:44]1>>[NH2:66][C:46]([C:49]1[S:53][C:52]2[CH:54]=[CH:55][C:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])=[CH:57][C:51]=2[CH:50]=1)([CH2:47][OH:48])[CH2:45][OH:44]
Reactant: CCCCCCCCc1ccc2sc(C3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2c1
Agent: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Product: CCCCCCCCc1ccc2sc(C(N)(CO)CO)cc2c1
Yield: 38 %

Procedure:
When tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was replaced with the product of Step C the similar procedure as described in Example 36, Step E gave the title compound (0.008 g, 38%) as light yellow solid. 1H NMR (CD3OD) 7.74 (d, 1H, J=8.28 Hz); 7.6 (s, 1H); 7.4 (s, 1H); 7.2 (dd, 2H, J=8.34, 1.59 Hz); 4.0 (d, 2H, J=11.46 Hz); 3.94 (d, 2H, J=11.46 Hz); 2.7 (t, 2H, J=7.53 Hz); 1.64 (b, 2H); 1.34-1.26 (b, 10H); 0.85 (t, 3H, J=4.8 Hz).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:32])([CH3:31])[O:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([C:17]([CH3:30])([CH3:29])[C:18](=[O:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]([Si:5]([CH3:32])([CH3:31])[O:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([C:17]([CH3:30])([CH3:29])[C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])([CH3:3])[CH3:4]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
ix)—A solution of compound 9a (39.4 g) in dry tetrahydrofuran (400 ml) was added dropwise to an ice-cooled suspension of lithium aluminium hydride (9.81 g) in tetrahydrofuran (490 ml). The mixture was stirred at room temperature for 1 h. The reaction was cooled to 0° C., and then quenched with a saturated aqueous solution of sodium sulfate. The reaction mixture was filtered over celite and the filtrate concentrated under reduced pressure to give (3β,20S)-20-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethylpregn-5-en-3-ol (compound 10a; 38.9 g), which was used in the following step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]C)=O.[C@H:12]1([C:24]2[S:28][C:27]([NH2:29])=[N:26][N:25]=2)[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[S:22][C:21]([NH2:23])=[N:20][N:19]=2)[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:29][C:27]1[S:28][C:24]([C@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]3[S:22][C:21]([NH:23][C:8](=[O:10])[CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:20][N:19]=3)[CH2:13]2)=[N:25][N:26]=1
Reactant: Nc1nnc([C@H]2CCC[C@H](c3nnc(N)s3)C2)s1
Reactant: COC(=O)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nnc([C@H]2CCC[C@H](c3nnc(NC(=O)Cc4ccccn4)s3)C2)s1
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
A mixture of methyl 2-(pyridin-2-yl)acetate (107.0 mg, 0.71 mmol), 5,5′-((1S,3S)-cyclohexane-1,3-diyl)bis(1,3,4-thiadiazol-2-amine) (200 mg, 0.71 mmol), cesium carbonate (762.7 mg, 1.42 mmol) in DMF (6 mL) was heated to 130° C. under nitrogen atmosphere and microwave for 45 min. The mixture was evaporated in vacuum to dryness. The residue was purified by a standard method to afford desired compound.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:8]1[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[N+]=[N-]>[Pd].C(O)C>[NH2:1][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[C:8]1[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1
Reactant: [N-]=[N+]=NCCCn1ccc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Pd]
Solvent: CCO
Product: NCCCn1ccc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
20 mg of 10% palladium on carbon were added to a solution of 100 mg (0.31 mmol) of 1-(3-azidopropyl)-3-(4-fluoropenyl)-2-(pyridin-4-yl)-1H-pyrrole [prepared as described in Step 22(iv) above] in 2 ml of ethanol. The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour, after which the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure. The residual solid was washed with diethylether to give 43 mg (yield 47%) of the title compound as a pale yellow powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[OH:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(O)c2cccnc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)c2cccnc2)cc1
Temperature: 70 °C
Yield: 234.8 %

Procedure:
Add manganese dioxide (1.44 g) to a stirred solution of [4-(tert-butyldimethylsilyloxymethyl)-phenyl]-pyridin-3-yl-methanol (360 mg, 0.303 mmol) in anhydrous 1,4-dioxane (25 mL). Heat the mixture to 70° C. overnight. Cool the reaction mixture to room temperature, filter through Celite® and wash with EtOAc. Concentrate the filtrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (1:1) to provide the desired intermediate (233 mg, 65%). GC-MS m/z: 327 (M+).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)CCC.[F-].[NH4+]>C1COCC1.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>[N:20]1[CH:21]=[CH:22][C:17]([C:2]2[CH:6]=[CH:5][O:4][C:3]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1occc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1occc1-c1ccncc1
Yield: 45.4 %

Procedure:
Ethyl 3-bromofuran-2-carboxylate (296 mg, 1.35 mmol) obtained in Step 1 of Reference Example 29, 4-(tri-n-butylstannyl)pyridine (550 mg, 1.51 mmol) and tetrakis(triphenylphosphine)palladium(0) (157 mg, 0.136 mmol) were dissolved in THF (10 mL), followed by stirring under heating and reflux for 4 hours. Aqueous ammonium fluoride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=2:3) to afford ethyl 3-(4-pyridyl)furan-2-carboxylate (133 mg, 45%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:23])[CH2:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>ClCCl>[Cl:26][C:18]([C:17]1[CH:21]=[CH:22][C:14]([CH2:13][CH2:12][N:11]([CH3:23])[C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:16]=1)=[O:19]
Reactant: O=S(Cl)Cl
Reactant: CN(CCc1ccc(C(=O)O)cc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CN(CCc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)benzoic acid (2.0 g, 6.38 mmol) in anhydrous dichloromethane (30 mL) was added dropwise thionyl chloride (1.52 g, 12.76 mmol) at 0° C. After the addition, the solution was stirred at room temperature overnight. Solvent was removed in vacuum to give benzyl 4-(chlorocarbonyl)phenethyl(methyl)carbamate. To a stirred solution of methyl 3-amino-2-hydroxybenzoate (0.71 g, 4.25 mmol) and pyridine (0.19 mL, 10.2 mmol) in anhydrous toluene (20 mL) was added dropwise a solution of benzyl 4-(chlorocarbonyl)phenethyl(methyl)carbamate (1.7 g, 5.1 mmol) in anhydrous toluene (5 mL). After the addition, the mixture was stirred at room temperature 30 min, then 80° C. for 1 h. The mixture was diluted with toluene, washed with water (30 mL×3), 1N hydrochloric acid (30 mL×3), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography ((silica gel, petroleum ether/ethyl acetate 15:1 to 4:1), to obtain methyl 3-(4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)benzamido)-2-hydroxybenzoate (1.9 g, yield 97%) as yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.82-2.87 (m, 5H), 3.49-3.53 (t, J=7 Hz, 2H), 3.94 (s, 1H), 4.98-5.06 (d, J=32 Hz, 2H), 6.98-7.02 (t, J=8 Hz, 1H), 7.26-7.39 (m, 7H), 7.66-7.68 (d, J=7.6 Hz, 1H), 7.89-7.91 (m, 2H), 7.94-7.96 (d, J=8 Hz, 1H), 9.61 (s, 1H), 10.92 (s, 1H); LC-MS (ESI) m/z: 463 (M+1)+.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[N+:21]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Cl)([O-:23])=[O:22]>CCO>[C:2]([O:6][C:7](=[O:13])[C@@H:8]([NH:9][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[N+:21]([O-:23])=[O:22])[CH:10]([CH3:11])[CH3:12])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NCc1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 79.5 %

Procedure:
To a solution of valine tert-butyl ester hydrochloride (1.5 g, 7.15 mmol) in EtOH (10 mL) was added triethylamine (2.09 mL, 15 mmol), followed after 10 minutes by 2-nitrobenzyl chloride (1.227 g, 7.15 mmol). The mixture was then stirred for 20 h under reflux before it was evaporated. The residue was purified by flash chromatograhy (petrol/ethyl acetate, 85/15) to afford the sub-title compound as a colorless oil (1.753 g, 80%). 1H NMR (400 MHz CDCl3) δ 0.93 (6H, m), 1.48 (9H, s), 1.83-1.96 (2H, m), 2.82 (1H, d), 3.92 (1H, d), 4.11 (1H, d), 7.39 (1H, t), 7.57 (1H, t), 7.65 (1H, d), 7.89 (1H, d).
Reaction SMILES: FC1C=C(C2C(C)=C(O)C(=O)N(CC(C)C)N=2)C=CC=1C.[C:22]([C:25]1[C:26](=[O:42])[N:27]([CH2:38][CH:39]([CH3:41])[CH3:40])[N:28]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[CH:30]=1)(O)=[O:23]>>[OH:23][CH2:22][C:25]1[C:26](=[O:42])[N:27]([CH2:38][CH:39]([CH3:40])[CH3:41])[N:28]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[CH:30]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)c(=O)n(CC(C)C)n2)cc1
Agent: Cc1ccc(-c2nn(CC(C)C)c(=O)c(O)c2C)cc1F
Product: Cc1ccc(-c2cc(CO)c(=O)n(CC(C)C)n2)cc1

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as slightly yellow needles (yield: 46.0%).
Reaction SMILES: [H-].[Na+].O1CCCC1.F[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16](=[N:37][OH:38])[CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[C:30](=[O:31])[N:29]3[CH2:32][CH2:33][CH2:34][CH2:35][C:28]3=[N:27][C:26]=2[CH3:36])[CH2:19][CH2:18]1>O>[F:15][C:13]1[CH:12]=[CH:11][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]4[C:30](=[O:31])[N:29]5[CH2:32][CH2:33][CH2:34][CH2:35][C:28]5=[N:27][C:26]=4[CH3:36])[CH2:19][CH2:18]3)=[N:37][O:38][C:9]=2[CH:14]=1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(C(=NO)c3ccc(F)cc3F)CC1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2
Yield: 77 %

Procedure:
To a suspension of 40 mg (0.9166 millimole) of 55% sodium hydride and 2 ml of tetrahydrofurane 0.1089 g (0.2532 millimole) of 3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is added. The reaction mixture is heated to boiling for an hour, whereupon 5 ml of water are added and the mixture is extracted twice with 10 ml of dichloromethane each. The combined organic phases are dried over magnesium sulfate and evaporated in vacuo. Thus 80 mg of the title compound are obtained, yield 77%. According to HPLC analysis the purity of the product is 97.5%.