Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.S(=O)(=O)=O.N1C=CC=CC=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]([CH3:45])[C@H:26]([CH2:42][CH2:43][OH:44])[CH2:27][N:28]2[C:32]3=[N:33][CH:34]=[CH:35][CH:36]=[C:31]3[C:30]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:29]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>ClCCl>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]([CH3:45])[C@H:26]([CH2:42][CH:43]=[O:44])[CH2:27][N:28]2[C:32]3=[N:33][CH:34]=[CH:35][CH:36]=[C:31]3[C:30]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:29]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1cn(C[C@@H](CCO)N(C)S(=O)(=O)c2ccc(F)cc2)c2ncccc12
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)Cc1cn(C[C@@H](CC=O)N(C)S(=O)(=O)c2ccc(F)cc2)c2ncccc12
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To DMSO (1 L, 1.41E+04 mmol) at room temperature was added pyridine sulfur trioxide (202.08 g, 1270 mmol) and the reaction mixture was stirred for 30 min at room temperature (solution A). In another flask, to a stirred solution of methyl {1-[(2R)-2-{[(4-fluorophenyl)sulfonyl](methyl)amino}-4-hydroxybutyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}acetate (273 g, 589 mmol) and Hunig's base (0.425 L, 2433 mmol) in dichloromethane (4 L) at −10° C. was added solution A dropwise over 30 min. The reaction was stirred at −10° C. for 1 h. then quenched by adding ½ saturated brine (4 L); the aqueous layer was neutralized with solid sodium bicarbonate. The layers were then separated and the organic layer was washed with ½ saturated brine (4 L), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography with ethyl acetate to provide the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.O>[N:34]([CH2:13][C:11]1[CH:10]=[N:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[CH:12]=1)=[N+:35]=[N-:36]
Reactant: Cc1cnn(-c2ccc(I)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1cnn(-c2ccc(I)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
A mixture of 1-(4-iodophenyl)-4-methyl-1H-pyrazole (1.70 g, 5.99 mmol), NBS (1.38 g, 7.75 mmol) and AIBN (0.30 g, 1.83 mmol) in CCl4 (25 mL) was heated at reflux for 1 hr. After being cooled to room temperature, the upper clear solution was decanted out and concentrated in vacuo. The residue was dissolved in DMF (10 mL), NaN3 (0.934 g, 14.3 mmol) was added. The mixture was stirred at room temperature overnight. H2O and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with hexane, then with 5% EtOAc in hexane to give 4-(azidomethyl)-1-(4-iodophenyl)-1H-pyrazole (0.70 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH:16]([C:18]1[CH:19]=[N+:20]([O-:30])[CH:21]=[CH:22][CH:23]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(c1cccnc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(c1ccc[n+]([O-])c1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 88.7 %

Procedure:
A solution of 2-(2,4-difluorophenyl)-3-(pyridin-3-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (diastereoisomeric pair B from Example 14) (1.00 g) and 85% w/w 3-chloroperoxybenzoic acid (1.30 g) in dichloromethane (20 ml) was stirred at room temperature for 18 hours and then evaporated. The residue was stirred with ether and the solid was filtered off and dried to give the title compound (0.93 g), m.p. 190°-193°.
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23]Br.[OH-].[Na+].Cl>C1COCC1.CC(CC)=O>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][O:12][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:1][CH:2]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: Fc1ccc(CBr)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCC(C)=O
Product: O=C(O)C=Cc1ccc(OCc2ccc(F)c(F)c2)cc1
Temperature: 50 °C
Yield: 73.4 %

Procedure:
2.5 g (15.2 mmol) p-cumaric acid is dissolved 100 ml ethyl methyl ketone. 4.21 g (30.5 mmol) potassium carbonate and 6.31 g (30.5 mmol) 3,4-difluorobenzyl bromide are added and the reaction mixture is hold at 70° C. over night. Dilution with water and extraction with ethyl acetate leaves a solid which is recrystallised from diethyl ether/n-hexane. The crude ester so obtained is dissolved in 100 ml THF and treated with 30.5 ml (30.5 mmol) of an aqueous 1 N sodium hydroxide solution. The mixture is heated to 50° C. for 6 hours, cooled and acidified with 1 N hydrochloric acid. The precipitate is filtered off and dried to yield 3.24 g (73%) of a colorless solid. MS: m/e=288.9 (M−H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH2:16])[C:5]2[N:6]([N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:7]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C1COCC1.[Cu]I.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:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:5]2[C:4]([NH2:16])=[N:3][C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:7][N:6]2[N:8]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1nc(Br)cn2nc(-c3ccco3)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cn2nc(-c3ccco3)nc2c(N)n1
Temperature: 50 °C

Procedure:
To a stirred solution of 6-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (500 mg, 1.78 mmol, see Examples 1 and 2 above) and (trimethylsilyl)acetylene (1.5 mL, 10 mmol) in a mixture of THF (10 mL) and TEA (5 mL) was added copper(I) iodide (68 mg, 0.36 mmol, 20 mol %) and PdCl2(PPh3)2 (190 mg, 0.27 mmol, 15 mol %). The reaction vessel was degassed and heated at 50° C. for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, and concentrated in vacuo to yield a crude product, which was purified by flash chromatography (silica gel, elution with 20% to 40% EtOAc/Hexane in volume) to afford the resulting 2-furan-2-yl-6-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine. The trimethylsilyl group was removed by treating a stirred solution of the crude material (2-furan-2-yl-6-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine) in wet MeOH (20 mL) with-Amberlyst A26 resin (2 g) for 1 hour. The suspension was filtered, and the resin was washed, sequentially with MeOH and THF. The filtrate was concentrated in vacuo to yield the desired 6-ethynyl-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (0.34 mg, 84% overall yield), which was used in the subsequent transformation without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH2:17])[CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O[CH:21](O)[C:22]([F:25])([F:24])[F:23])C.O>C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C@@H:10](/[N:17]=[CH:21]/[C:22]([F:25])([F:24])[F:23])[CH2:11][CH2:12][C:13]([F:14])([F:16])[F:15])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](N)CCC(F)(F)F
Reactant: CCOC(O)C(F)(F)F
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@H](CCC(F)(F)F)/N=C/C(F)(F)F

Procedure:
A solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-trifluoro-pentan-2-amine (3.00 g, 11.06 mmol) and trifluoroacetaldehyde ethyl hemiacetal (1.6 g, 11.1 mmol) in benzene (20 mL) was refluxed for 2 hours during which time water was collected in a Dean-Stark trap. The solvent was removed in vacuo yielding crude (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-trifluoro-N-[(1E)-2,2,2-trifluoroethylidene]pentan-2-amine.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12]Cl.[OH:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19]>ClCCl>[CH3:10][O:11][CH2:12][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COCCl
Reactant: COC(=O)c1cccc(O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cccc(C(=O)OC)c1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
At about 0° C., diisopropylethylamine (1.7 g, 13.1 mmol) and methoxymethyl chloride (635 mg, 7.9 mmol) were sequentially added to a solution of methyl 3-hydroxybenzoate (1 g, 6.6 mmol) in dry dichloromethane (10 mL). The resulting mixture was maintained at ambient temperature for about 3 hours. Following standard extractive workup, the crude product was purified by flash column chromatography on silica gel (2×16 cm, petroleum ether/ethyl acetate=10/1 elution) to give the title product (1.03 g, 80%). 1H NMR (300 MHz, CDCl3) δ 7.71-7.69 (m, 2H), 7.36 (dd, 1H, J=7.8, 1.8 Hz), 7.25 (dd, 1H, J=7.8, 1.8 Hz), 5.22 (s, 2H), 3.92 (s, 3H), 3.50 (s, 3H); LC-MS: m/z=197 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([NH:9][S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[Li+].[CH3:26][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([N:9]([CH3:26])[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)C1CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)cyclopropane-sulfonamide (see Example 2) (283.9 mg, 0.61 mmol) in 3 ml anhydrous THF was added at −78° C. a IM solution of LHMDS (0.6 ml, 0.6 mol) and the solution was stirred for 10 min at this temperature. Then, methyl iodide (0.8 ml, 1.824 g, 12.9 mmol) was added and the mixture was warmed to room temperature and stirred for 7 h. The solvent was removed and the residue extracted using EtOAc and brine. The organic fractions were dried using Na2SO4 and the solvent was removed. The obtained crude product was purified using flash-column chromatography (Si, EtOAc/Hexanes 1:2, Rf=0.45). Yield: 205 mg, 70%). 1H-NMR (500 MHz, CDCl3): δ=7.41-7.39 (d, 1H, J=10 Hz), 7.30-7.29 (d, 1H, J=8.0 Hz), 7.23-7.20 (m, 1H), 6.98-6.93 (q, 1H, J=8.5 Hz), 6.60 (s, 1H, br), 6.51-6.47 (m, 1H), 3.23 (s, 3H), 2.46-2.42 (m, 1H), 1.19-1.16 (m, 2H), 1.04-1.02 (m, 2H); m/z=481 [M−1]−.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:20]=[C:19]([NH:21][S:22]([CH:25]=[CH2:26])(=[O:24])=[O:23])[CH:18]=[C:17]([C:27]([F:30])([F:29])[F:28])[CH:16]=1)=[O:13].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(Cl)Cl>C(O)(C)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]([C:27]([F:29])([F:30])[F:28])[CH:18]=[C:19]([NH:21][S:22]([CH2:25][CH2:26][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)(=[O:24])=[O:23])[CH:20]=1)=[O:13]
Reactant: C=CS(=O)(=O)Nc1cc(NC(=O)c2c[nH]c3ccccc3c2=O)cc(C(F)(F)F)c1
Reactant: C1CCNCC1
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(Nc1cc(NS(=O)(=O)CCN2CCCCC2)cc(C(F)(F)F)c1)c1c[nH]c2ccccc2c1=O
Temperature: 75 °C

Procedure:
A mixture of 4-oxo-N-[3-(trifluoromethyl)-5-(vinylsulfonamido)phenyl]-1,4-dihydroquinoline-3-carboxamide (50 mg, 0.11 mmol), piperidine (18 μL, 1.6 eq) and LiClO4 (20 mg, 1.7 eq) was suspended in a 1:1 solution of CH2Cl2:isopropanol (1.5 mL). The mixture was refluxed at 75° C. for 18 h. After this time, LCMS analysis showed >95% conversion to the desired product. The crude mixture was purified by reverse-phase HPLC to provide 4-oxo-N-[3-[2-(1-piperidyl)ethylsulfonylamino]-5-(trifluoromethyl)phenyl]-H-quinoline-3-carboxamide (318) as a yellowish solid (15 mg, 25%). 1H-NMR (d6-Acetone, 300 MHz) δ 8.92 (br s, 1H), 8.4 (d, J=8.1 Hz, 1H), 8.05 (br s, 1H), 7.94 (br s, 1H), 7.78 (br s, 2H), 7.53-751 (m, 1H), 7.36 (br s, 1H), 3.97 (t, J=7.2 Hz, 2H), 3.66 (t, J=8 Hz, 2H), 3.31-3.24 (m, 6H), 1.36-1.31 (m, 4H); ESI-MS 489.1 m/z (MH+).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[CH:8][N:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([O-])(=O)C.[K+].[N:23](Cl)=[O:24]>C(O)(=O)C.C(OC(=O)C)(=O)C>[N:23]([N:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[N:7][CH:8]=1)[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[O:24]
Reactant: CCCCCc1ccc(NC(=O)C(C)C)cn1
Reactant: O=NCl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCCCc1ccc(N(N=O)C(=O)C(C)C)cn1

Procedure:
24.8 g of N-(2-pentyl-5-pyridyl)-isobutyramide (boiling point 167°-171°/0.27 bar; obtainable by reacting 2-chloro-5-nitropyridine with Na-2-butylmalonic acid diethyl ester to give 2-(5-nitro-2-pyridyl)-2-butylmalonic acid diethyl ester, hydrolysis and decarboxylation to give 2-pentyl-5-nitropyridine, hydrogenation on 10% strength Pd-C in methanol at 40°-50° under 1 bar to give 2-pentyl-5-aminopyridine and acylation with isobutyric anhydride) are dissolved in a mixture of 110 ml of acetic acid and 50 ml of acetic anhydride, 49 g of anhydrous potassium acetate are added, and a solution of 6.9 g of nitrosyl chloride in 27 ml of acetic anhydride is then added at 0°. N-nitroso-N-(2-pentyl-5-pyridyl)-isobutyramide is formed as the intermediate and is not isolated. After the mixture has been stirred at 0° for 15 minutes, it is poured onto ice and extracted five times with 140 ml of thiophene each time. The phases are separated, the organic phase is kept at 0° and made into a slurry with 22 g of K2CO3 and 35 g of Na2SO4, and the slurry is decanted. The organic phase is warmed at 50° and, when the evolution of gas has ended, boiled for 2 hours, and evaporated and the residue is separated on silica gel using toluene. 2-(2-Pentyl-5-pyridyl)-thiophene, boiling point 180°-185°/0.013 bar, c.p. -45° is obtained; a little 3-(2-pentyl-5-pyridyl)-thiophene, boiling point 170°-180°/0.015 bar, c.p. -80°, is also formed.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11][CH3:12])[CH2:3]1.Cl[C:14]1[C:15]2[C:22]([CH3:23])=[CH:21][S:20][C:16]=2[N:17]=[CH:18][N:19]=1.C(N(CC)CC)C>C(O)C>[CH3:12][O:11][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH2:10][CH:2]([NH:1][C:14]1[C:15]3[C:22]([CH3:23])=[CH:21][S:20][C:16]=3[N:17]=[CH:18][N:19]=1)[CH2:3]2
Reactant: COc1cccc2c1CC(N)C2
Reactant: Cc1csc2ncnc(Cl)c12
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cccc2c1CC(Nc1ncnc3scc(C)c13)C2
Yield: 94.1 %

Procedure:
Using 2-amino-4-methoxyindan (27 mg, 0.17 mmol) synthesized in the above b) in Reference Production Example 5, 4-chloro-5-methylthieno[2,3-d]pyrimidine (31 mg, 0.17 mmol), triethylamine (71 μl, 0.51 mmol), and ethanol (1.5 ml), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (50 mg, 0.16 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O>C(O)C.[Pd]>[CH3:1][O:2][CH:3]([O:17][CH3:18])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[NH2:14]
Reactant: COC(CNCc1cc(C)ccc1[N+](=O)[O-])OC
Agent: [Pd]
Solvent: CCO
Product: COC(CNCc1cc(C)ccc1N)OC

Procedure:
The crude aminoacetal obtained in step (c) is dissolved in 700 ml of ethanol and is hydrogenated at room temperature and at atmospheric pressure, in the presence of 3 g of palladium catalyst (10% Pd on carbon). After the catalyst is filtered off and the filtrate evaporated, the heading compound remains as an orange oil, which is converted into the hydrochloride using methanolic hydrochloric acid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O.[NH:34]1[C:38]([NH2:39])=[N:37][N:36]=[N:35]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([N:11]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH:39][C:38]3[NH:37][N:36]=[N:35][N:34]=3)=[O:30])=[CH:26][CH:25]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:9][CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Cn1c(N(Cc2ccc(C(=O)O)cc2)C2CCC(C(C)(C)C)CC2)nc2ccc(O)cc21
Reactant: Nc1nnn[nH]1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cn1c(N(Cc2ccc(C(=O)Nc3nnn[nH]3)cc2)C2CCC(C(C)(C)C)CC2)nc2ccc(O)cc21
Temperature: 40 °C

Procedure:
To the product of Example 12 Step B (0.04 mmol), 1H-tetraazol-5-amine monohydrate (0.12 mmol, 12 mg), HOBt (0.08 mmol, 12 mg) and EDC (0.08 mmol, 15 mg) in 1 mL of DMF was added DIEA (0.08 mmol, 14 μL). The reaction was heated at 40° C. for 2.5 h, then concentrated under reduced pressure. The residue was taken up in ca. 2:1 dioxane/H2O and acidified with TFA, then purified by reverse-phase chromatography (Condition B). The product was lyophilized directly, affording the title compound as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 12.35 (br s, 1H), 9.81 (br s, 1H), 8.01 (d, 2H), 7.52 (d, 2H), 7.28 (d, 2H), 6.91 (unres. d, 1H), 6.79 (dd, 1H), 4.75 (s, 2H), 3.69 (s, 3H), 2.01 (m, 2H), 1.83 (m, 2H), 1.69 (m, 2H), 1.16 (m, 2H), 1.04 (m, 11H), 0.85 (s, 9H). One proton obscured by H2O. MS (ESI): m/z 503 (M+H). HPLC A: 1.85 min.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[C:17]([S:19][C:20]([S:23][C:24]2[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:27]([OH:34])=[C:26]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:25]=2)([CH3:22])[CH3:21])[CH:16]=[C:15]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:6]=1[O:7][CH2:8][CH2:9][C@H:10]([OH:14])[C:11](O)=[O:12])([CH3:4])([CH3:3])[CH3:2].B>C1COCC1>[C:1]([C:5]1[CH:18]=[C:17]([S:19][C:20]([S:23][C:24]2[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:27]([OH:34])=[C:26]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:25]=2)([CH3:22])[CH3:21])[CH:16]=[C:15]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:6]=1[O:7][CH2:8][CH2:9][C@H:10]([OH:14])[CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(OCC[C@H](O)C(=O)O)c(C(C)(C)C)c1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(OCC[C@H](O)CO)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 47.8 %

Procedure:
A 100 mL round bottom flask equipped with a nitrogen adapter and temperature probe was charged with 1.42 g (2.3 mmol, 1 eq) of 4-{2,6-di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-1-methyl-ethylsulfanyl]-phenoxy}-2(S)-hydroxy-butyric acid (Ex-10C), 25 mL THF and cooled to 0° C. The solution was treated with 6.9 mL (6.9 mmol, 3 eq) of 1.0 M borane in THF, warmed to 25° C. and monitored by HPLC. After stirring 6 hours at 25° C., the reaction was cooled using an ice bath, quenched with 15 mL of methanol and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% EtOAc/hexanes gradient to 80% EtOAc/hexanes) and dried in vacuo to yield 660 mg (1.1 mmol, 47% yield) of 4-{2,6-di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-1-methyl-ethylsulfanyl]-phenoxy}-butane-1,2(S)-diol as a white solid, mp 110–112° C. 1H NMR (300 MHz, CDCl3) δ: 7.56 (s, 2H), 7.46 (s, 2H), 5.38 (s, 1H), 3.86–4.06 (m, 3H), 3.71–3.78 (m, 1H), 3.52–3.60 (m, 1H), 2.54 (d, 1H, J=4.08 Hz), 1.97–2.12 (m, 2H), 1.92 (t, 1H, J=6.19 Hz), 1.46 (s, 6H), 1.46 (s, 18H), 1.45 (s, 18H). Anal. calcd for C35H56O4S2: C69.49, H9.33, S10.60; found: C68.86, H9.25, S10.39HRMS (EI+) m/z+Na: calc. 627.3518; found 627.3539.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[N:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[C:16](=O)([O:20]CC)[O:17][CH2:18][CH3:19]>O1CCCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][C:16]([O:17][CH2:18][CH3:19])=[O:20])[N:11]=1
Reactant: Cc1cccnn1
Reactant: CCOC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccnn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.8 %

Procedure:
Lithium diisopropylamide (2M in tetrahydrofuran, 6.83 g, 63.7 mmol) was added dropwise to a stirred solution of 3-methylpyridazine (5.0 g, 53.12 mmol) in anhydrous tetrahydrofuran (80 mL) at −78° C. under a nitrogen atmosphere over a period of 20 min. The mixture was allowed to warm to room temperature. The mixture was stirred for 1 h at room temperature and cooled again to −78° C. Diethyl carbonate (12.57 g, 106.2 mmol) in anhydrous tetrahydrofuran (20 mL) was added at −78° C. over a period of 20 min. The reaction mixture was allowed to warm to room temperature, stirred for 16 h and partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organics were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified via column chromatography (100-200 mesh silica gel, 50-80% ethyl acetate in petroleum ether) to afford ethyl 2-(pyridazin-3-yl)acetate (600 mg). MS (ES+) (M+H) 167.1569.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[S:12][C:13]([N+:16]([O-])=O)=[CH:14][CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1>CO.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[S:12][C:13]([NH2:16])=[CH:14][CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3cc(Cl)cnc3[nH]2)s1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(-c2nc3cc(Cl)cnc3[nH]2)s1
Reaction time: 2 h
Yield: 44.3 %

Procedure:
6-Chloro-2-(5-nitro-2-thienyl)-3H-imidazo[4,5-b]pyridine (Example 275) (0.10 g, 0.36 mmol) was dissolved in methanol (10 ml). A catalytic amount of Raney nickel was added. The solution was shaken for 2 h under hydrogen pressure (3 atm.). The catalyst was filtered off and the crude material was purified by column chromatography (EtOAc) to give the title product (0.04 g, 44%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[Sn](CCCC)(CCCC)CCCC)([CH3:3])[CH3:2].[C:27]([O:33][CH2:34][N:35]1[C:39]2=[N:40][CH:41]=[C:42](Br)[N:43]=[C:38]2[C:37]([C:45](=[O:51])[NH:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:36]1)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C.[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>[C:27]([O:33][CH2:34][N:35]1[C:39]2=[N:40][CH:41]=[C:42]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=4)[N:9]([CH3:13])[N:8]=3)[N:43]=[C:38]2[C:37]([C:45](=[O:51])[NH:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:36]1)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)NC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C(C)C)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)c1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)NC(C)(C)C)cn3COC(=O)C(C)(C)C)nn2C

Procedure:
A mixture 5-isopropyl-1-methyl-3-(tributylstannyl)-1H-indazole, (2-bromo-7-(tert-butylcarbamoyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl pivalate (0.408 g, 1 mmol), CuI (0.06 g, 0.32 mmol) and Pd(PPh3)4 (0.06 g, 0.052 mmol) in 40 mL of DMF was stirred at 80° C. under nitrogen for 4 hours. The solvent was removed under reduced pressure and the residue was triturated with water (15 mL) and petroleum ether (30 mL) then decanted and dried to give crude (7-(tert-butylcarbamoyl)-2-(5-isopropyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl pivalate (0.15 g) as a yellow solid, which was used into next step without further purification. LCMS: (M+H)+=505.