Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[OH:20].S(=O)(=O)(O)O.[CH2:26](O)[CH3:27]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([O:18][CH2:26][CH3:27])=[O:17])=[CH:11][C:10]=1[OH:20]
Reactant: CC(C(=O)O)c1ccc(-c2ccc(F)cc2F)c(O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc(-c2ccc(F)cc2F)c(O)c1

Procedure:
A solution of 2-(2',4'-difluoro-2-hydroxy-4-biphenylyl)propionic acid (4.5 g.) in absolute ethanol (50 ml.) containing concentrated sulphuric acid (2 ml.) was refluxed overnight (16 hours). After distillation of ethanol the residue was poured onto ice-water and the product was isolated in ether. The extracts were washed with dilute sodium bicarbonate dried and evaporated. The solid residue thus obtained was purified by two crystallisations from light petrol (b.p. 62°-68° C.), to give ethyl 2-(2',4'-difluoro-2-hydroxy-4-biphenylyl)propionate, m.p. 72°-73° C.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26]I)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C-:30]#[N:31].[Na+]>CN(C)C=O.O>[N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26][C:30]#[N:31])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC[C@@H]1C[C@@H](OC(=O)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2S,4R)-1-(p-Nitrobenzyloxycarbonyl)-2-iodomethyl-4-benzoyloxypyrrolidine (5.24 g) was dissolved in 26 ml of dry dimethylformamide, and 539 mg of sodium cyanide was added thereto, followed by stirring at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography to give (2R,4R)-1-(p-nitrobenzyloxycarbonyl)-2-cyanomethyl-4-benzoyloxypyrrolidine
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[C:12]4[CH:24]=[CH:23][S:22][C:13]=4[C:14](=[O:21])[NH:15][C:16]=3[CH:17]=[CH:18][C:19]=2[OH:20])=[CH:6][CH:5]=1)[CH3:3].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[OH:20][C:19]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:21])[C:13]3[S:22][CH:23]=[CH:24][C:12]=3[C:11]=2[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([C@@H:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH3:3])=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](N)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Product: C[C@H](NS(C)(=O)=O)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 56.3 %

Procedure:
Following the procedure outlined for Example 301, (S)-9-[4-(1-aminoethyl)phenyl]-8-hydroxythieno[2,3-c]quinolin-4(5H)-one (100 mg, 0.30 mmol) was reacted with methanesulfonyl chloride (100 mg, 0.89 mmol) to afford the desired product (70 mg, 56%) as a light brown solid: 1H NMR (500 MHz, CD3OD) δ 5.89-7.55 (m, 2H), 7.52 (d, J=5.4 Hz, 1H), 7.38 (d J=8.9 Hz, 1H), 7.30-7.28 (m, 2H), 7.15 (d, J=8.9 Hz, 1H), 6.00 (d, J=5.4 Hz, 1H), 4.71 (q, J=7.1 Hz, 1H), 2.82 (s, 3H), 1.61 (d, J=7.0 Hz, 3H); ESI MS m/z 415 [C20H18N2O4S2+H]+; HPLC >99% (AUC), tR=12.43 min.
Reaction SMILES: [F-:1].[K+].[CH3:3][C:4]([C:7]1[N:12]=[C:11](Cl)[C:10]([CH:14]([CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:8]=1)([CH3:6])[CH3:5].C1OCCOCCOCCOCCOCCOC1.O>S1(CCCC1)(=O)=O>[CH3:3][C:4]([C:7]1[N:12]=[C:11]([F:1])[C:10]([CH:14]([CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:8]=1)([CH3:6])[CH3:5]
Reactant: [F-]
Reactant: CCOC(=O)C(c1cnc(C(C)(C)C)nc1Cl)C(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CCOC(=O)C(c1cnc(C(C)(C)C)nc1F)C(C)C
Temperature: 150 °C
Yield: 45 %

Procedure:
A stirred suspension of dry potassium fluoride (1.41 g) and ethyl (RS)-2-[2-(2-methylprop-2-yl)-4-chloropyrimidin-5-yl]-3-methylbutyrate (1.88 g) in dry sulpholane (14 cm3) in the presence of 18-crown-6 (0.38 g) was heated to 150° C. for a period of 24 hours, under an atmosphere of dry nitrogen. After cooling to the ambient temperature (ca. 22° C.), the reaction mixture was poured into water, and extracted into ethyl acetate. The organic layer was washed with water and brine, dried and the solvent evaporated under reduced pressure. The residual brown liquid was purified by column chromatography on silica gel, using dichloromethame as eluent, to give ethyl (RS)-2-[2-(2-methylprop-2-yl)-4-fluoropyrimidin-5-yl]-3-methylbutyrate (0.8 g) as an orange liquid.
Reaction SMILES: CS(O[C:6]1[N:11]=[C:10]2[C:12]([Cl:16])=[N:13][CH:14]=[CH:15][C:9]2=[N:8][C:7]=1[CH3:17])(=O)=O.O1CCOCC1.[ClH:24]>CCOC(C)=O>[Cl:24][C:6]1[N:11]=[C:10]2[C:12]([Cl:16])=[N:13][CH:14]=[CH:15][C:9]2=[N:8][C:7]=1[CH3:17]
Reactant: Cl
Reactant: Cc1nc2ccnc(Cl)c2nc1OS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc2ccnc(Cl)c2nc1Cl
Temperature: 70 °C
Yield: 49.6 %

Procedure:
A glass microwave reaction vessel was charged with 5-chloro-2-methylpyrido[3,4-b]pyrazin-3-yl methanesulfonate (160 mg, 0.585 mmol), 1,4-Dioxane (1 mL) and hydrogen chloride (4 M in 1,4-dioxane, 0.73 mL, 2.92 mmol) (Sigma Aldich). The reaction mixture was stirred and heated in an oil bath at 70° C. for 1 h, then cooled to RT. The mixture was diluted with EtOAc (50 mL) and washed with sat. NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated to give 3,5-dichloro-2-methylpyrido[3,4-b]pyrazine (62 mg, 0.290 mmol, 49% yield) as a brown solid. MS (ESI, pos. ion) m/z: 213.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.[C:12](Cl)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[C:12]([NH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Nc1ccc2nc(S)[nH]c2c1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)Nc1ccc2nc(S)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.6 %

Procedure:
5 g of 5-amino-2-mercaptobenzimidazole was dissolved in 50 ml of pyridine and 7.95 g of dodecanoyl chloride was added dropwise thereto under cooling with ice. After stirring, for 3 hours at room temperature, the solution was poured into ice-water. The formed crystals were filtered off and recrystallized from water-containing methanol to obtain 10.9 g of compound (8).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(N)c1cccc(C(F)(F)F)c1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cccc(C(F)(F)F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(3-trifluoromethylphenyl)acetate (prepared from 2-(hydroxyimino)-2-(3-trifluoromethylphenyl)acetic acid [CAS 179811-81-5] using General Procedures G and R above), the title compound was prepared as a solid (mp=133-134° C.). The product was purified by tituration from EtOAc/hexanes.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH3:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH3:19])=[CH:14][C:13]=1[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: CSc1cc(Cl)nc(C)n1
Reactant: CC(c1cnc(F)c(B2OC(C)(C)C(C)(C)O2)c1)N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1cc(-c2cc(C(C)N3CCOCC3)cnc2F)nc(C)n1
Temperature: 90 °C
Yield: 78.8 %

Procedure:
To a 20 mL microwave vials was added 4-chloro-2-methyl-6-(methylthio)pyrimidine (0.175 g, 1.002 mmol), 2-fluoro-5-(1-morpholinoethyl)pyridin-3-ylboronic acid (Example 339 Step 3) (0.305 g, 1.202 mmol), trans-dichlorobis(triphenyl-phosphine)palladium (II) (Strem) (0.056 g, 0.080 mmol), sodium carbonate (JT Baker) (0.531 mg, 5.01 mmol), DME (10 mL), and water (2.5 mL). The vial was degassed by bubbling N2 for 5 min then sealed off and microwave heated at 90° C. for 20 min. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 10% to 20% acetone in hexanes) to afford the product as white solid (275 mg). MS (ESI pos. ion) m/z: 349.1. 1H NMR (300 MHz, CDCl3) δ ppm 1.43 (d, J=6.72 Hz, 3H) 2.33-2.46 (m, 2H) 2.48-2.58 (m, 2H) 2.61 (s, 3H) 2.74 (s, 3H) 3.52 (q, J=6.58 Hz, 1H) 3.71 (t, J=4.46 Hz, 4H) 7.55 (s, 1H) 8.25 (s, 1H) 8.56 (dd, J=9.43, 2.27 Hz, 1H).
Reaction SMILES: O[CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]1=2.C1C=CC(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:34]([CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]1=2)=[N+:35]=[N-:36]
Reactant: O=S(=O)(Oc1ccc2c(c1)CCCC2O)C(F)(F)F
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NC1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 0 °C

Procedure:
To a solution of trifluoro-methanesulfonic acid 5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl ester (11.2 g, 37.9 mmol, 1.0 eq) in THF (150 mL) at RT was added DPPA (Aldrich, 11.1 mL, 51.6 mmol, 1.36 eq). The resulting mixture was cooled to 0° C., then DBU (Aldrich, 7.7 mL, 51.6 mmol, 1.36 eq) was added slowly through a syringe. The reaction was warmed to RT and stirred over the weekend. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (400 mL), washed with saturated NH4Cl (twice), water, and brine, dried over Na2SO4, and concentrated in vacuo. The crude was purified by flash chromatography (5% EtOAc-hexane) to provide the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[NH2:31][C:32]1[CH:36]=[CH:35][NH:34][N:33]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(O)(=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:31][C:32]2[CH:36]=[CH:35][NH:34][N:33]=2)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNc2cc[nH]n2)cc1)Cc1nc2ccccc2[nH]1
Yield: 22.4 %

Procedure:
Using General Procedure B: To a stirred solution of 4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (199 mg, 0.50 mmol) and 3-aminopyrazole (60 mg, 0.72 mmol) in THF (5 mL) and acetic acid (0.2 mL) was added NaBH(OAc)3 (166 mg, 0.78 mmol) and the resultant mixture stirred at room temperature for 2.5 days. Purification of the crude material by radial chromatography on silica gel gel (2 mm plate, CH2Cl2/MeOH/NH4OH, 100:1:1 then 50:1:1) afforded the desired amine (52 mg, 23%) as a white foam.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[S:20][C:21]3[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[S:20][C:21]3[CH:27]=[C:26]([NH:28][C:1](=[O:3])[CH3:2])[CH:25]=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(-c2nc3ccc(N)cc3s2)cn1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-c2nc3ccc(NC(C)=O)cc3s2)cn1
Temperature: 25 °C
Yield: 39.3 %

Procedure:
Acetylchloride (3 μL, 0.037 mmol) and pyridine (3 μL, 0.037 mmol) was added to a sol. of 2-(6-methoxypyridin-3-yl)-1,3-benzothiazol-6-amine (9 mg, 0.034 mmol) in DCM (1 mL). The r.m. was stirred at r.t. o.n. Half of the solvent was distilled of in vacuo and a few drops of hexane were added. The precipitated solid was collected and dried in vacuo, to give the title compound (4 mg) as a white solid. 1H NMR δ 10.30 (s, 1H) 8.91 (d, 1H) 8.57 (d, 1H) 8.39 (dd, 1H) 8.03 (d, 1H) 7.63 (dd, 1H) 7.08 (d, 1H) 4.02 (s, 3H) 2.16 (s, 3H); MS m/z (M+H) 300, (M−H) 298.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27](O)(=O)[CH3:28]>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:27]([CH3:28])[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CC(=O)O
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and acetic acid, the title compound was obtained in 76% purity by HPLC. MS(ESI+): m/z=377.0.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=2[F:13])[CH2:3][CH2:2]1.CCCCCC.C([Li])CCC.[C:25](=[O:27])=[O:26].C(=O)([O-])O.[Na+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:25]([OH:27])=[O:26])=[C:8]([F:12])[C:7]=2[F:13])[CH2:2][CH2:3]1
Reactant: O=C=O
Reactant: Fc1cccc(OCC2CC2)c1F
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCC2CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(cyclopropylmethoxy)-2,3-difluorobenzene (19.0 g) in THF (200 mL) was added 1.6 M n-butyllithium hexane solution (64.5 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hr. To the reaction mixture was added dry ice, and the mixture was allowed to warm to room temperature, and stirred for 15 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was washed with diethyl ether, and acidified with 6N hydrochloric acid. This mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained solid was washed with diethyl ether to give the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].N1C=CC=CC=1.[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46])=[O:41]>ClCCl>[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40](=[O:41])[C:42]1[CH:50]=[CH:49][CH:48]=[C:44]([C:45]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4](=[O:5])[NH:6][C:7]2[N:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[N:8]=2)=[O:46])[CH:43]=1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ncn(-c2cccc(C(F)(F)F)c2)n1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ncn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 2.5 °C
Yield: 14.9 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzamide (150 mg, 0.35 mmol, 1.00 equiv) in dichloromethane (20 mL), and pyridine (83 mg, 1.05 mmol, 3.01 equiv). This was followed by dropwise addition of a solution of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoyl chloride (130 mg, 0.42 mmol, 1.20 equiv) in dichloromethane (10 mL) with stirring at 0-5° C. The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 30 mL of dichloromethane. The resulting mixture was washed with 1×20 mL of NH4Cl and 2×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 36.7 mg (15%) of a yellow solid. 1H-NMR (400 MHz, DMSO, ppm): δ 11.43-11.33(m, 2H), 9.70(s, 1H), 9.43(s, 1H), 8.77(s, 1H), 8.26-8.18 (m, 3H), 8.06-7.93 (m, 2H), 7.86-7.79(m, 2H), 7.68-7.62(m, 2H), 7.52(s, 1H), 7.30-7.28(d, J=6.9 Hz, 1H), 4.59-4.57(m, 1H), 4.18-3.83(m, 27H), 3.44(s, 3H), 3.27-3.26 (m, 5H), 3.18 (s, 3H), 2.96(s, 4H), 1.69(s, 4H), 1.59-1.52(m, 3H). MS (ES, m/z): 705 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][CH:6]([F:26])[O:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[C:11]([NH:13][C:14]1[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:16]([OH:18])=[O:17])=O>ClCCCl>[F:5][CH:6]([F:26])[O:7][C:8]1[CH:9]=[C:10]([C:11]2[O:17][C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Nc1ccccc1C(=O)O)c1cccc(OC(F)F)c1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: O=c1oc(-c2cccc(OC(F)F)c2)nc2ccccc12
Reaction time: 4 h

Procedure:
25 parts by weight of 3-difluoromethoxybenzoyl chloride and 12.2 parts by weight of triethylamine are added over 15 minutes, from 2 separate feeds, to a stirred mixture of 16.6 parts by weight of anthranilic acid in 360 parts by weight of 1,2-dichloroethane at 25°-30° C. After stirring for 2 hours at 25° C., the reaction mixture is extracted with 0.5 N hydrochloric acid and with water. The organic phase is then extracted with four times 100 parts of 0.5 N sodium hydroxide solution, and the extracts are stirred into dilute hydrochloric acid. After filtration and drying, 30.4 parts by weight, corresponding to 82% of theory, of N-(3-difluoromethoxybenzoyl)-anthranilic acid of melting point 186°-191° C. are obtained. 8.33 Parts by weight of thionyl chloride are introduced into a stirred mixture of 18 parts by weight of N-(3-difluoromethoxybenzoyl)-anthranilic acid in 250 parts by weight of 1,2-dichloroethane at 25° C.; the mixture is then stirred for 4 hours under reflux. When it has cooled, the reaction mixture is extracted with 100 parts by volume of ice-water and 100 parts by volume of 0.5 N sodium hydroxide solution and is chromatographed over neutral aluminum oxide. 12 parts by weight, corresponding to 71% of theory, of 2-(3'-difluoromethoxy-phenyl)-3,1-benzoxazin-4-one, of melting point 84°-87° C., are obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:15]([CH:19]=1)[C:16](O)=[O:17])[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:68][C:69]([CH3:73])([CH3:72])[CH2:70][OH:71]>CN(C=O)C>[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:15]([CH:19]=1)[C:16]([NH:68][C:69]([CH3:73])([CH3:72])[CH2:70][OH:71])=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(N)CO
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)NC(C)(C)CO)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
To a solution of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid (0.203 mmol, 94.9 mg), HBTU (0.203 mmol, 79.3 mg), diisopropyl ethyl amine (0.34 mmol, 0.0592 mL) in DMF (1 mL) was added 2-amino-2-methyl-propan-1-ol (0.45 mmol, 42.2 mg). It was stirred at room temperature for 20 min. The reaction mixture was partitioned between ethyl acetate (12 mL) and saturated aq. sodium bicarbonate solution (12 mL). The ethyl acetate layer was washed again with saturated aq. sodium bicarbonate solution (2×12 mL) and dried over sodium sulfate. The organic solvents were removed in vacuo to give 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide (87.7 mg).
Reaction SMILES: [CH3:1][C:2]1[N:10]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:9]2[C:4](=[N:5][C:6]([N:20](C(OC(C)(C)C)=O)[NH:21][C:22](OC(C)(C)C)=O)=[CH:7][CH:8]=2)[CH:3]=1.[C:36](O)(=O)C>>[CH3:36][C:22]1[N:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[N:10]([S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:12])=[O:13])[C:9]=3[CH:8]=[CH:7][C:6]2=[N:20][N:21]=1
Reactant: Cc1cc2nc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CC(=O)O
Product: Cc1cc2c(ccc3nnc(C)n32)n1S(=O)(=O)c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of di-tert-butyl 1-[2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (19.53 g, 38.86 mmol, from Step 3) in acetic acid (200 mL) was heated at 120° C. overnight. Precipitate was filtered off, and the filtrate was concentrated in vacuo. Dichloroethane (15 mL) was added, and the suspension was heated at reflux for 15 minutes. Upon cooling to 0° C., the solid product was isolated by filtration and dried at 40° C. under vacuum to give an off-white solid (5.94 g). Solvent was removed from the filtrate in vacuo and the above procedure was repeated using DCE (6 mL) to afford additional solid (3.6 g). Additional product was obtained by flash chromatography of the filtrate, (eluting with a gradient of 0-1% MeOH/DCM containing 1% NH4OH). The chromatography afforded product as a glass, which was recrystallized from MeOH (6 mL). Upon recrystallization, product was isolated as white crystals and air dried (2.19 g). Yield: (11.7 g, 92%).