Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:23])[CH2:4][CH2:5][C:6]2([CH2:19][CH2:20][CH2:21][CH3:22])[C:14]=1[C:13]1[C:8](=[C:9]([Cl:18])[C:10]([O:16]C)=[C:11]([F:15])[CH:12]=1)[CH2:7]2.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[C:3](=[O:23])[CH2:4][CH2:5][C:6]2([CH2:19][CH2:20][CH2:21][CH3:22])[C:14]=1[C:13]1[C:8](=[C:9]([Cl:18])[C:10]([OH:16])=[C:11]([F:15])[CH:12]=1)[CH2:7]2
Reactant: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(OC)c(Cl)c1C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(O)c(Cl)c1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-9a-butyl-8-chloro-6-fluoro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (31 mg, 0.077 mmol) in anhydrous dichloromethane (0.5 mL) was cooled in a dry ice-acetone bath (−78° C.) and the solution treated with 1M boron tribromide in dichloromethane (0.231 mL, 0.231 mmol). The cooling bath was removed and the mixture was stirred at room temperature for one hour. The mixture was partitioned between EtOAc (20 mL) and water (20 mL) containing 2N HCl (2 mL). The organic phase was washed with brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate, developing with 10% EtOAc in CHCl2. The product band was eluted with EtOAc, the eluent evaporated under vacuum, and the residue lyophilized from benzene plus a few drops of EtOH to afford 4-bromo-9a-butyl-8-chloro-6-fluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C([Li])(C)(C)C.CN(C)[CH:27]=[O:28]>O1CCCC1>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:5]2[N:6]=[CH:7][C:2]([CH:27]=[O:28])=[CH:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccc(CNc2ccc(Br)cn2)cc1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=Cc1ccc(NCc2ccc(C(F)(F)F)cc2)nc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
To a solution of (5-bromo-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine (17, 3.55 g, 0.0107 mol, commercially available, or prepared as described in Example 10) in tetrahydrofuran (150 mL) was added tert-butyllithium (13.2 mL, 1.70 M in pentane, 0.0224 mol) slowly under an atmosphere of nitrogen at −78° C. over 10 minutes. The reaction mixture was stirred at −78° C. for 90 minutes. N,N-Dimethylformamide (2.2 mL, 0.028 mol) was added slowly into the reaction mixture. The reaction mixture was stirred at −78° C. for 2 hours, then allowed to warm to room temperature. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate, brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a light yellow solid (18, 1.67 g, 56%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.Cl.[CH2:14]([NH:16][CH:17]([CH3:21])[CH2:18][CH2:19][NH2:20])[CH3:15]>ClCl.[OH-].[Na+]>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([N:16]([CH2:14][CH3:15])[CH:17]([CH3:21])[CH2:18][CH2:19][NH:20][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CCNC(C)CCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: ClCl
Agent: [Na+]
Product: CCN(C(C)CCNS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 39.4 %

Procedure:
A solution of p-toluenesulfonyl chloride (17.01 g, 89.2 mmol) in CH2 Cl2 (300 mL) was added to a solution of II (8.89 g, 47.0 mmol) in 1N NaOH (300 mL) which had been cooled to 0° C. After addition was complete, the biphasic mixture was stirred for 14 hours (0° C. to room temperature). The layers were separated and the aqueous portion was extracted with CH2Cl2 (2×50 mL). The combined organic phase was washed with 1N HCl (2×100 mL) and (100 mL) and evaporated in vacuo. Column chromatography on silica gel eluting with 3% EtOH/CHCl3 produced 7.46 g (39%) of III. NMR δ 0.77 (d, 3 H, J=7), 1.15 (t, 3 H, J=7), 1.45-1.76 (m, 2 H), 2.40 (s, 6 H), 2.79-3.25 (m, 4 H), 3.70-4.08 (m, 1 H), 5.47 (t, 1 H, J=7), 7.13-7.81 (m, 8 H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[C:19]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C:20]=4[N:21]=3)=[CH:12][CH:11]=2)[NH:4][C:3]1=[O:40].Cl>O1CCOCC1>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[C:19]4[CH2:25][CH2:24][NH:23][CH2:22][C:20]=4[N:21]=3)=[CH:12][CH:11]=2)[NH:4][C:3]1=[O:40]
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cc(=O)n(C)c(=O)[nH]3)cc2)nc2c1CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cc(=O)n(C)c(=O)[nH]3)cc2)nc2c1CCNC2
Reaction time: 2 h

Procedure:
Step 2—Synthesis of compound um: (S)-Tert-butyl 2-(4-(1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-ylamino)phenyl)-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.196 g, 0.000357 mol) and 4.0 M of Hydrogen chloride in 1,4-Dioxane (5.00 mL) were mixed and stirred for 2 hours. The mixture was concentrated, diluted with sat NaHCO3 and extracted three times with 10% MeOH in dichloromethane. The aqueous layer was lyophilized, slurried in MeOH, vacuum filtered, and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.95 (s, 1H), 8.28 (d, J=8.7, 2H), 8.23 (s, 1H), 7.28 (d, J=8.7, 2H), 6.52 (s, 1H), 5.02 (s, 1H), 4.11 (d, J=6.4, 1H), 3.88 (d, J=11.1, 3H), 3.71 (dd, J=11.3, 2.8, 1H), 3.65-3.56 (m, 3H), 3.08 (s, 3H), 2.99-2.92 (m, 1H), 2.87-2.80 (m, 1H), 2.58 (s, 2H), 1.24 (d, J=6.6, 3H). LC/MS-m/z+450.2 (M+H)+
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:16](=[O:17])[NH:15][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.[BrH:24]>>[BrH:24].[OH:2][C:3]1[CH:4]=[C:5]([C:11]2[C:16](=[O:17])[NH:15][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(-c2cnc(-c3ccccc3)[nH]c2=O)cc1OC
Agent: Br
Product: O=c1[nH]c(-c2ccccc2)ncc1-c1ccc(O)c(O)c1
Reaction time: 2 h

Procedure:
5-(3,4-Dimethoxyphenyl)-2-phenyl-6(1H)-pyrimidinone (7.4 g) are stirred in 250 ml of 48% aqueous hydrobromic acid at 100° C. for 24 hours and at 140° C. for 24 hours. After cooling the yellow crystals obtained are filtered off, washed with water and suspended in 200 ml of water. Sodium hydrogen carbonate is added thereto until pH 7.5 has been reached. After stirring for 2 hours the product is filtered off, washed with water and dried in a vacuum at room temperature over potassium hydroxide. There are obtained 6 g of 5-(3,4-dihydroxyphenyl)-2-phenyl-4(3H)-pyrimidinone hydrobromide as a yellow powder of m.p.>250° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[CH3:11][O:12][CH2:13][CH2:14]Br>C(O)C>[CH2:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:14][CH2:13][O:12][CH3:11])[CH3:2]
Reactant: COCCBr
Reactant: CCNCc1ccccc1
Solvent: CCO
Product: CCN(CCOC)Cc1ccccc1
Yield: 47 %

Procedure:
The synthesis of BnEA was carried out in a manner similar to that of BnEO (process 2) using N-ethylbenzylamine (15 mL, 0.101 mol), bromoethyl methyl ether (0.101×1.2 mol), and ethanol (100 mL) as a solvent. BnEA (9.17 g, 47.46 mmol, yield 47%) was obtained as a yellow-orange clear liquid. [Purification was carried out by medium pressure silica gel column chromatography (n-hexane:ethyl acetate=3:2).]
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:22][CH2:21][N:20]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:19][CH2:18]2)=[CH:5][N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.[ClH:50]>>[ClH:50].[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:18][CH2:19][N:20]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:21][CH2:22]2)=[CH:5][NH:4][N:3]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(=O)N4CCOCC4)CC3)c2c1
Agent: Cl
Product: Cc1n[nH]cc1-c1ccc2nccc(N3CCN(C(=O)N4CCOCC4)CC3)c2c1

Procedure:
90 mg 4-[6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-quinolyl]piperazin-1-yl-(morpholino)methanone obtained in Example 196 and 1 mL of 5 N hydrochloric acid were reacted in the same manner as in Example 163, to give 36 mg of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]=2[NH:4][CH:3]=1.[CH3:12]N(C)C=O.[H-].[Na+].CI>C(OCC)(=O)C>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]=2[N:4]([CH3:12])[CH:3]=1
Reactant: Clc1ncnc2c(Br)c[nH]c12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1cc(Br)c2ncnc(Cl)c21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To 7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (147 mg), N,N-dimethylformamide (10 mL) was added, and NaH (36 mg) was further added thereto, followed by stirring for 30 min. Subsequently, methyl iodide was added thereto, and the reaction mixture was heated to 50° C. and stirred for 2 hours. After completion of the reaction, the reaction mixture was mixed with ethyl acetate and washed with water. The washed mixture was dried over anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[Si]([C:20]#[N:21])(C)(C)C.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]=[C:8]2[C:20]#[N:21]
Reactant: COc1ccc2c(c1OC)CCCC2=O
Reactant: C[Si](C)(C)C#N
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc2c(c1OC)CCC=C2C#N
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
Tetralone 7 (1.7 g, 8.25 mmol) was added as a slurry in freshly distilled toluene (25 mL) to a dried flask with magnetic stirring. TMSCN (1.42 mL, 10.7 mmol) was added dropwise. After stirring for 10 min, BF3.OEt2 (1.57 mL, 12.38 mmol) was added with a syringe. The reaction was stirred at room temperature for 3 h, until no starting material remained. The reaction was quenched by pouring over 30 mL ice water and stirring vigorously. To this aqueous mixture were added 20 mL of Et2O, and the layers were separated. The aqueous layer was extracted twice more with Et2O and once with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure to afford a tan solid (1.7 g, 7.9 mmol, 96%) that was recrystallized from MeOH to yield fine, colorless needles; mp 138-140° C. (lit.36 mp 137-139° C.). 1H NMR: (300 MHz, CDCl3): δ 7.18 (d, 1H, J=8 Hz, ArH); 6.80 (d, 1H, J=8 Hz, ArH); 6.75 (t, 1H, J=4.6 Hz, ArCH2CH2CH); 3.88 (s, 3H, ArOCH3); 3.76 (s, 3H, ArOCH3); 2.87 (t, 2H, J=8 Hz, ArCH2); 2.44 (m, 2H, ArCH2CH2). EIMS (M+)=215.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:16][C:15]([C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]([O:25]CC)=[O:24])[N:21]=3)=[N:14][N:13]=2)[CH2:8][CH2:7]1.[OH-].[Na+].Cl>C1COCC1.CO>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:16][C:15]([C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]([OH:25])=[O:24])[N:21]=3)=[N:14][N:13]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)Cn1nnc(-c2nnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)s2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cn1nnc(-c2nnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)s2)n1
Temperature: 25 °C

Procedure:
A solution of ethyl [5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate (134 mg, 0.28 mmol) in THF/MeOH (2:1) (v/v) (4.6 mL) was treated with aqueous 1 N NaOH (1.5 mL). The reaction mixture was stirred at room temperature until TLC indicated disappearance of the starting material. The reaction mixture was poured into aqueous aqueous 0.5 N HCl, extracted with EtOAc, washed with brine. The organic layer was dried (Na2SO4) and filtered. Evaporation of the solvent was followed by trituration in a mixture of Et2O/heptane with stirring for 1 h at room temperature. After this time, the title compound was collected by filtration as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([F:12])=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>CCO.N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([F:12])=[CH:6][C:3]=1/[CH:4]=[CH:14]/[C:15]([OH:17])=[O:16]
Reactant: COc1cc(F)c(C=O)cc1F
Reactant: O=C(O)CC(=O)O
Solvent: CCO
Solvent: c1ccncc1
Product: COc1cc(F)c(/C=C/C(=O)O)cc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A 250 mL round bottom flask was charged with 2,5-difluoro-4-methyoxybenzaldehyde (commercially available from Manchester Organics Ltd., UK) (18.45 g, 107.2 mmol), malonic acid (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (12.27 g, 117.9 mmol), and 10:1 EtOH/pyridine (27 mL). The mixture was stirred overnight at 70° C. under a reflux condenser and cooled to 0° C. for 2 hours. The precipitated solid was filtered, rinsed with ether, and dried in vacuo to afford H3.1 (16.96 g, 74% yield) as a white powder.
Reaction SMILES: [Br-:1].[Li+].C1(C)C=CC(S(O[CH2:13][CH2:14][C:15]2([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=O)=O)=CC=1>CC(C)=O>[Br:1][CH2:13][CH2:14][C:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OCCC2(O)CCCCC2)cc1
Agent: [Li+]
Solvent: CC(C)=O
Product: OC1(CCBr)CCCCC1

Procedure:
A stirred solution of lithium bromide (70 g) and 1-(2-p-toluenesulphonyloxyethyl)cyclohexanol (16.4 g) in acetone (350 ml) was heated under reflux for 1 hour. The cooled reaction mixture was partially concentrated in vacuo and then partitioned between ether (300 ml) and water. The ether phase was washed with water and brine, dried and concentrated in vacuo to give 1-(2-bromoethyl)cyclohexanol [H; n=1, R1 +R2 =--(CH2)5 --] as an oil.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@@H:12]([CH2:22][O:23][CH3:24])[O:11][C@H:10]1[N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][C:28]([CH2:49][O:50][CH:51]1[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]1)=[N:29][C:30]=2[NH:34][CH2:35][CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:37]1([CH:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:35][NH:34][C:30]2[N:29]=[C:28]([CH2:49][O:50][CH:51]3[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]3)[N:27]=[C:26]3[C:31]=2[N:32]=[CH:33][N:25]3[C@H:10]2[C@H:9]([OH:8])[C@H:13]([OH:14])[C@@H:12]([CH2:22][O:23][CH3:24])[O:11]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COC4CCN(C)CC4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COC4CCN(C)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
N-(9-[(2R,3R,4R,5R)-3,4-Bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-2-{[(1-methyl-4-piperidinyl)oxy]methyl}-9H-purin-6-yl)-N-(2,2-diphenylethyl)amine (68 mg, 0.08 mmol) (preparation 49) was dissolved in stirred tetrahydrofuran (10 ml), then acetic acid (0.2 ml, 0.2 mmol) added followed by a 1 molar solution of tetra-n-butylammonium fluoride (0.2 ml, 0.2 mmol). The reaction mixture was stirred at room temperature for 1 hr and then more 1 molar solution of tetrabutylammonium fluoride (0.5 ml, 0.5 mmol) was added. The reaction mixture was stirred for another hour and then partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The ethyl acetate phase was separated, washed with brine and dried with anhydrous sodium sulfate. This was evaporated to give a clear oil which was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (95:5) increasing in polarity to dichloromethane:methanol:ammonia (90:10:1) to give the title compound (20 mg) as a foam. MS: 589 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.OO.NC(N)=[O:14].FC(F)(F)C(OC(=O)C(F)(F)F)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N+:3]=1[O-:14]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NC(N)=O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ccc(Cl)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Chloropyridine-5-carbonitrile (7.01 g) was dissolved in acetonitrile (70 mL), and urea hydrogen peroxide addition compound (10 g) was added. Trifluoroacetic anhydride was added dropwise to the reaction mixture under ice-cooling and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to aqueous sodium thiosulfate solution and the mixture was extracted with chloroform. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give 2-chloro-5-cyanopyridine 1-oxide (0.779 g) as a white solid.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][S:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:11])[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:21][C:22]1[N:23]=[C:24]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([F:40])([F:39])([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[O:25][CH:26]=1.O>CN(C=O)C>[F:38][S:35]([F:36])([F:37])([F:39])([F:40])[C:32]1[CH:33]=[CH:34][C:29](/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][S:10]([CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[O:11])=[CH:18][CH:17]=3)[N:23]=2)=[CH:30][CH:31]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: O=S(CCn1ccnn1)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(S(F)(F)(F)(F)F)cc3)n2)cc1
Reaction time: 0.25 h
Yield: 17.1 %

Procedure:
14 mg (0.50 mmol) 95% sodium hydride were given to a solution of 126 mg (0.50 mmol) 4-(2-[1,2,3]Triazol-1-yl-ethanesulfinylmethyl)-phenol in 3.0 ml DMF and stirred for 15 min. 173 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 6 ml water the resulting precipitate was washed with water (2×), water/methanol 1:1 (2×), ethyl acetate/n-heptane 3:1 (1×), little ethyl acetate (1×), diethyl ether (1×) and dried in vacuum at 40° C. Further purification by chromatography on silica gel (eluent:ethyl acetate/methanol 15:1) and stirring of the isolated product with little ether and ethyl acetate and drying gave 48 mg (17%) white powder.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:6]=1)C.[Li+].[OH-]>C1COCC1>[C:15]([O:14][C:12]([NH:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:19])=[O:3])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1cccc(NC(=O)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Temperature: 75 °C
Yield: 40807.7 %

Procedure:
To the crude 3-tert-butoxycarbonylamino-benzoic acid ethyl ester (˜2.0 g, 0.00754 mmol) added THF (15 mL), and 0.5M LiOH (15 mL). The mixture was heated for two hours at 75° C. and the THF was removed in vacuo after cooling. The precipitate was filtered from the remaining mixture and the filtrate was transferred to a separatory funnel. The aqueous layer was washed with dichloromethane (3×) and was acidified to pH˜5 using 1M HCl. The product was then extracted with ethyl acetate, washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. 730 mg of 3-tert-Butoxycarbonylamino-benzoic acid (white solid) was isolated. 1H NMR (DMSO-d6) δ (ppm): 9.58 (s, 1H), 8.16 (s, 1H), 7.63 (d, 1H), 7.54 (d, 1H), 7.37 (t, 1H), 1.49 (s, 9H)
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27][C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=4[F:35])[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[CH:15]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([O:27][C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])[CH:22]=[N:21]2)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Oc2c(F)cccc2F)cc1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H](O)CO)n1)n1ncc(Oc2c(F)cccc2F)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A solution of 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (1.21 g, 2.33 mmol) in methanol (23 mL, 0.1 M) at 25° C. was treated with para-toluenesulfonic acid monohydrate (66.3 mg, 0.34 mmol). The reaction was stirred at 25° C. overnight. After this time, the reaction was diluted with ethyl acetate (200 mL) and was washed with a saturated aqueous sodium bicarbonate solution (2×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were dried over magnesium sulfate, filtered, rinsed and then concentrated in vacuo. Silica gel column chromatography (AnaLogix 80 g, 1-10% methanol/methylene chloride) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.86 g, 77%) as a white solid as a mixture of diastereomers; ES+-HRMS m/e calcd for C22H25N5O5F2 [M+H+] 478.1897 found 478.1896. 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.8 Hz, 3H) 0.89 (d, J=6.8 Hz, 3H) 1.38-1.51 (m, 1H) 1.80 (ddd, J=13.6, 9.4, 4.3 Hz, 1H) 2.10-2.26 (m, 1H) 3.21-3.51 (m, 2H) 3.71-3.81 (m, 1H) 3.82-3.92 (m, 1H) 4.09 (dd, J=13.6, 3.9 Hz, 1H) 4.70 (t, J=5.6 Hz, 1H) 4.91-4.96 (m, 1H) 5.52 (dd, J=11.0, 3.9 Hz, 1H) 6.04 (d, J=2.7 Hz, 1H) 6.36 (d, J=2.1 Hz, 1H) 7.35-7.43 (m, 2H) 7.43-7.52 (m, 1H) 7.53 (d, J=2.1 Hz, 1H) 8.28 (d, J=2.7 Hz, 1H) 10.82 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]2[C:8](=[CH:9][C:10]([CH3:24])=[C:11]([C:19](=[O:23])[CH2:20][CH2:21][CH3:22])[CH:12]=2)[N:7]=1)=[O:5])C.[OH-].[Na+:26]>C(O)C>[CH2:17]([O:16][C:14]1[C:13]2[C:8](=[CH:9][C:10]([CH3:24])=[C:11]([C:19](=[O:23])[CH2:20][CH2:21][CH3:22])[CH:12]=2)[N:7]=[C:6]([C:4]([O-:5])=[O:3])[CH:15]=1)[CH3:18].[Na+:26]
Reactant: CCCC(=O)c1cc2c(OCC)cc(C(=O)OCC)nc2cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(=O)c1cc2c(OCC)cc(C(=O)[O-])nc2cc1C
Reaction time: 0.25 h

Procedure:
6 g of 4-ethoxy-6-butyryl-7-methylquinoline-2-carboxylic acid ethyl ester are dissolved in 150 ml of ethanol, 9 ml of 2N sodium hydroxide solution are added and the mixture is hydrolysed for 15 minutes at room temperature. The precipitated crystals are filtered with suction and recrystallised from water. Sodium 4-ethoxy-6-butyryl-7-methylquinoline-2-carboxylate having a melting point of above 250° C. is obtained. By dissolving in water and acidifying, 4-ethoxy-6-butyryl-7-methylquinoline-2-carboxylic acid is obtained.