Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:7]2[CH2:20][CH2:21][N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:6]12)=[O:4].C[O-].[Na+]>CO>[C:26]([O:25][C:23]([N:22]1[CH:6]2[CH:7]([N:8]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:9][CH:5]2[C:3]([OH:4])=[O:2])[CH2:20][CH2:21]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)OC(C)(C)C)C12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)O)CN2C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 101.7 %

Procedure:
A solution of 74 (1.4 g, 3.5 mmol) in MeOH (20 mL) was added to a solution of NaOMe (0.34 g, 6.3 mmol) in MeOH at ambient temperature. The reaction mixture was stirred for 16 h and then concentrated. The residue was diluted with EtOAc, washed successively with 1M HCl, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 72 as an orange-colored foam (1.39 g) that was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]([CH3:30])([CH3:29])[C:7]#[C:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC#N.Cl[Pd]Cl>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]([C:7]1[N:18]([CH2:19][CH2:20][OH:21])[C:10]2[C:9]([CH:8]=1)=[CH:14][C:13]([N+:15]([O-:17])=[O:16])=[CH:12][CH:11]=2)([CH3:30])[CH3:29])[CH3:2]
Reactant: CCOC(=O)CC(C)(C)C#Cc1cc([N+](=O)[O-])ccc1NCCO[Si](C)(C)C(C)(C)C
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)CC(C)(C)c1cc2cc([N+](=O)[O-])ccc2n1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
A solution of 5-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-5-nitro-phenyl}-3,3-dimethyl-pent-4-ynoic acid ethyl ester (600 mg, 1.34 mmol) and PdCl2 (650 mg) in CH3CN (30 mL) was heated at reflux overnight. The resulting mixture was extracted with EtOAc (30 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was dissolved in THF (20 mL) and TBAF (780 mg, 3.0 mmol) was added. The mixture was stirred at room temperature for 1 h, the solvent was removed under vacuum, and the residue was purified by chromatography on silica gel (10% ethyl acetate/petroleum) to afford 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-methyl-butyric acid ethyl ester (270 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 8.45 (d, J=2.1 Hz, 1H), 8.05 (dd, J=2.1, 9.0 Hz, 1H), 6.36 (d, J=9.0 Hz, 1H), 6.48 (s, 1H), 4.46 (t, J=6.6 Hz, 2H), 4.00-3.91 (m, 4H), 2.76 (s, 2H), 1.61 (s, 6H), 0.99 (t, J=7.2 Hz, 1H), 0.85 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: [CH2:1]=[C:2]([C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:4].O1CCOCC1>[Pd].C(OCC)C>[CH3:25][C:21]1([CH3:26])[CH2:20][CH2:19][C:18]([CH3:27])([CH3:28])[C:17]2[CH:16]=[C:15]([CH:2]([CH3:1])[C:3]([NH:5][C:6]3[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=3)=[O:4])[CH:24]=[CH:23][C:22]1=2
Reactant: C=C(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
650 mg (1.7 mmol) of 4-(α-methylene-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetamido)benzoic acid, 100 mg of palladium on charcoal (10%) and 100 ml of dioxane are introduced into a reactor. The mixture is hydrogenated at room temperature and under a pressure of 7 bars for 2 h, the catalyst is filtered off and the filtrate is evaporated. The residue obtained is ground in the minimum amount of ethyl ether, filtered off and dried. 580 mg (89%) of acid, melting point 195°-6° C., are obtained.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:23])[CH2:21][CH3:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.O>C(Cl)Cl>[CH3:23][CH:20]([CH2:21][CH3:22])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1
Reactant: CCC(C)Cc1ccc(-c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCC(C)Cc1ccc(-c2ccc(O)cc2)cc1
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A solution of 33 m moles(8.2 g) of boron tribromide in 25 ml of methylene chloride was cooled to -70° C., and a solution of 28 m moles(7.0 g) of 4'-methoxy-4-(2-methylbutyl)biphenyl in 150 ml of methylene chloride was added dropwise thereto. The mixture was returned to room temperature in 8 hours, and then stirred for five hours. After addition of water, the reaction mixture was extracted with methylene chloride, then purified by column chromatography to obtain 4.0 g of 4'-(2-methylbutyl)-4-hydroxybiphenyl. (yield: 60%)
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:11][CH:12]([CH3:26])[CH2:13][N:14]([CH2:22][CH:23]([OH:25])[CH3:24])[CH2:15][CH2:16][NH:17][CH2:18][CH:19]([OH:21])[CH3:20].COC1C=CC(O)=CC=1.CO>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH3:20][CH:19]([OH:21])[CH2:18][N:17]([CH2:9][CH:8]([OH:10])[CH3:7])[CH2:16][CH2:15][N:14]([CH2:22][CH:23]([OH:25])[CH3:24])[CH2:13][CH:12]([OH:11])[CH3:26].[C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: CC(O)CNCCN(CC(C)O)CC(C)O
Agent: COc1ccc(O)cc1
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C(C)C(=O)[O-]
Product: CC(O)CN(CCN(CC(C)O)CC(C)O)CC(C)O
Temperature: 25 °C

Procedure:
(VI-a): Glycidyl methacrylate (5.0 g, 35.5 mmol) was added, dropwise, to a solution of N,N,N'-tris(2-hydroxypropyl)ethylenediamine (V-a) (8.3 g, 35.5 mmol) in 10 mL of CH2Cl2 at room temperature. 4-Methoxyphenol (0.03 g) was added to prevent polymerization. The reaction was maintained for 72 hours at room temperature, then warmed to 30° C. for an additional 24 hours. The reaction was followed by TLC (4 percent MeOH in CCl4 ; glycidyl methacrylate Rf 0.69). Quadrol methacrylate (VI-a) was obtained in quantitative yield after removal of the solvent. The product was further purified by dissolving 5 g of (VI-a) in 200 mL distilled water followed by addition of sodium chloride to saturation. The product, which separated out as an oil, was collected, dissolved in CH2Cl2, and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed to give Quadrol-methacrylate [yield, 53 percent; IR(neet):3350(broad OH); 1720(C=O); 1640(C=C); NMR(CDCl3 ): δ6.2(s, 1H); 5.6(s, 1H); 4.0(broad m, 6); 2.5(broad m, 12H); 2.0 (s, 3H); 1.1(d, 9H)].
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1O.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH2:42]>C(#N)C.[Pd].[Cu](I)I>[N+:8]([C:6]1[C:7]2[CH:14]=[C:13]([CH2:12][OH:15])[O:42][C:2]=2[CH:3]=[CH:4][CH:5]=1)([O-:10])=[O:9]
Reactant: C#CCO
Reactant: O
Reactant: O=[N+]([O-])c1ccc(O)c(I)c1
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc2oc(CO)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
2-Iodo-4-nitrophenol (30 mg, 0.11 mmol) and propargyl alcohol (19 mg, 0.33 mmol) were suspended in a mixture of water (1 ml) and acetonitrile (0.2 ml). Triethylamine (34.3 mg, 0.34 mmol), Pd/C (10%, 2.6 mg, 5.6 μmol), triphenylphosphine (5.9 mg, 22.6 μmol) and copper iodide (2.15 mg, 11.3 μmol) were then added and the heterogeneous mixture was heated at 80° C. while stirring for 3 hours. After cooling the reaction mixture was filtered over celite, and a mixture of water (40 ml) and ethyl acetate (20 ml) was added to the filtrate. After separation of the phases the aqueous phase was extracted with ethyl acetate (2×10 ml) and the combined organic phase was washed with a saturated solution of NaHCO3, then brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography to give 17.2 mg of pure 4-nitro-benzofuran-2-yl-methanol (78% yield).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9]O>>[C:1]1([OH:2])[CH:3]=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:3]1([O:4][CH3:9])[C:1](=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:2]
Reactant: Oc1ccccc1O
Reactant: CO
Product: COc1ccccc1O
Product: Oc1ccccc1
Reaction time: 14 h

Procedure:
When the temperature of the catalyst stratum reached 260° C. in Example 43 and 300° C. in Example 44, a starting compound mixture consisting of catechol and methyl alcohol in a mixing molar ratio of 1:3.44 was evaporated in an evaporator, and the resultant starting compound mixture gas was fed in a feeding rate of 10.5 g/min. together with a nitrogen gas into the reaction tube for 14 hours, to etherify catechol with methyl alcohol and to produce a dihydric phenol compound monoalkylether, i.e., guaiacol. The reaction mixture gas discharged from the reaction tube was cooled to a temperature of 40° C. The resultant liquefied product was collected from the reaction mixture.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)([O-:5])=[O:4].[O-][Cl:16].[Na+].Cl>O>[Cl:16][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[N+:3]([O-:5])=[O:4])[NH:10][N:9]=1
Reactant: [O-]Cl
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cccc2[nH]nc(Cl)c12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a mixture of NaOH (0.500 g, 12.5 mmol) in H2O (15.0 mL) was added 4-nitroindazole (0.500 g, 3.07 mmol) after which it was heated until a red solution formed. The solution was immediately placed in an ice-water bath for 15 minutes before NaClO (6.00 mL, 5.25%, 4.50 mmol) was added. The mixture was stirred at 0° C. for 5 hour, the pH adjusted to 7 with dilute HCl and extracted with ethyl acetate. The combined organic layer was washed with H2O, concentrated under reduced pressure and purified by flash chromatography to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.17 (m, 1H), 8.57 (m, 1H), 8.77 (m, 1H), 14.17 (s, 1H); MS (DCI/NH3) m/Z 197[M+H]+.
Reaction SMILES: [CH:1]1([N:6]=[C:7]=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:10][C@H:11]([CH:30]([CH3:32])[CH3:31])[C:12]([N:14]1[CH2:19][CH2:18][C@@:17]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)([OH:20])[C:16]([CH3:29])([CH3:28])[CH2:15]1)=[O:13].C1COCC1>C(N(CC)CC)C>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C@@:17]2([OH:20])[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C@H:11]([NH:10][C:7]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])[CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2([CH3:28])[CH3:29])=[CH:26][CH:25]=1
Reactant: O=C=NC1CCCC1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)[C@@H](NC(=O)NC1CCCC1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction tube was charged with cyclopentyl isocyanate (9 μL), (R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride (30 mg) and THF (2 mL). Triethylamine (11 μL) was added and the reaction mixture was shaken overnight at rt. After this time, the resulting solution concentrated and purified by preparative silica gel chromatography (100% EtOAc to 20% MeOH/CH2Cl2) to provide Example 511. MS found: (M+H)+=450.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[N:18]1([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.N1C(C)=CC=CC=1C>>[CH2:27]([O:26][C:24]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]3)[CH:7]=2)[CH2:20][CH2:19]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: Cc1cccc(C)n1
Product: CC1CCN(c2cc(N3CCN(C(=O)OCc4ccccc4)CC3)ccc2[N+](=O)[O-])CC1

Procedure:
The procedure of Example 4, step (b) was followed using 400 mg (1.57 mmol) of 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine (as prepared in the Example 12, step (a)) and 910 mg (4.71 mmol) of benzyl 1-piperazinecarboxylate (except that 549 μL (4.71 mmol) of 2,6-lutidine was also added) to afford, after chromatography on a 70-g silica SPE column with 40% EtOAc-hexane, 178 mg (45%) of unreacted 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine and 245 mg (64% based on recovered starting material) of the title compound as a yellow resin: Mass spectrum (ESI, m/z): Calcd. for C24H30N4O4, 439.2 (M+H), found 439.2.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][C:11]1=[O:23])[CH2:5][C:6]([F:9])([F:8])[CH3:7].O1CCCC1.O.[OH-].[Li+]>O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:13]1[CH2:14][N:10]([C@@H:4]([CH2:5][C:6]([F:9])([F:8])[CH3:7])[C:3]([OH:24])=[O:2])[C:11](=[O:23])[CH:12]=1
Reactant: COC(=O)[C@H](CC(C)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(F)(F)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
In a flask was placed (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-pentanoic acid methyl ester (139 mg, 0.39 mmol) in a 1:1 solution of tetrahydrofuran:water (8 mL) which was treated with lithium hydroxide monohydrate (35 mg, 0.78 mmol) and stirred for 1.5 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran and partioned between 1N aqueous hydrochloric acid (10 mL) and ethyl acetate (10 mL). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to afford (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-pentanoic acid (130 mg, 96%) as a light amber foam: HR-ES-MS m/z calculated for C15H14NO4ClF2 [M+H]+ 346.0652, observed 346.0652.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:35][CH2:34][O:33][CH2:32]1>>[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[CH2:35][CH2:34][O:33][CH2:32]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCCC1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 220 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(4-bromobutyl)tetrahydrofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.C([O-])([O-])=O.[K+].[K+].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[C:20]2[C:27]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30](=[O:38])(=[O:37])[NH:29][N:28]=1.Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CC#N.O.C(Cl)Cl>[C:44]([O:43][C:41](=[O:42])[CH2:40][N:22]1[C:23]2[C:19](=[CH:18][C:17]([F:16])=[CH:25][CH:24]=2)[C:20]([C:27]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30](=[O:37])(=[O:38])[N:29]([CH2:4][C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[Cl:1])[N:28]=2)=[C:21]1[CH3:26])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: ClCc1ccccc1Cl
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1c(C2=NN(Cc3ccccc3Cl)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Chlorobenzyl chloride (9 μL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: Br[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH2:3].[Li]C(C)(C)C.Cl[Si:16](Cl)([CH3:18])[CH3:17].[C:20]1([CH:26]([OH:31])[CH2:27][C:28]([CH3:30])=[CH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(CC)CC>CCOCC.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:17][Si:16]([CH3:18])([CH2:3][CH:2]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[O:31][CH:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:27][C:28]([CH3:30])=[CH2:29]
Reactant: C=C(Br)CCCCCC
Reactant: C[Si](C)(Cl)Cl
Reactant: C=C(C)CC(O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Li]C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(C)CC(O[Si](C)(C)CC=CCCCCC)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-octene (2.85 g, 15.0 mmol 1.2 equiv) in Et2O (15 mL) was added dropwise with t-BuLi (1.5 M, 20.0 mL, 30.0 mmol, 2.4 equiv) under N2 atmosphere at −78° C. (internal). The pale-yellow, cloudy mixture was stirred for 1 h at −78° C. (internal). The mixture was then added to a solution of dichlorodimethylsilane (3.8 mL, 31.25 mmol, 2.5 equiv) in Et2O (15 mL) via cannula at −78° C. (internal). The mixture was allowed to warm to room temperature and was stirred for 2 h whereupon a white solid precipitated. After removal of solvent and excess dichlorodimethylsilane under reduced pressure, hexane (50 mL) was added and the solids were removed by Schlenk filtration. After removal of the solvent, the residue was dissolved in CH2Cl2 (5 mL). The solution was then added to a solution mixture of 1-phenyl-3-methyl-3-buten-1-ol (2.03 g, 12.5 mmol, 1.0 equiv), 4dimethylaminopyridine (229 mg, 1.88 mmol, 0.15 equiv), and Et3N (2.6 mL, 18.8 mmol, 1.5 equiv) in CH2Cl2 (10 mL) under N2 atmosphere at 0° C. (internal). The mixture was allowed to warm to room temperature and was stirred for 2 h. The mixture was then poured to ice water (20 mL) and aqueous phase was extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent was removed by rotary evaporation. The residue was purified by chromatography (silica gel, hexane) followed Kugelrohr distillation under reduced pressure to afford 2.85 g (69%) of E-5 as a colorless liquid.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17](N1C=CN=C1)([N:19]1C=CN=[CH:20]1)=O.Cl.CNC.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](=[O:13])[N:19]([CH3:20])[CH3:17])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
Amine preparation: to a stirring solution of BOC-isonipecotic acid (400 mg) in DMF (4 mL) was added 1,1′-carbonyldiimidazole (560 mg). The reaction mixture was stirred overnight and then dimethylamine hydrochloride (280 mg) and triethylamine (0.48 mL) were added. After 5 h the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent was removed in vacuo to yield 4-dimethylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester. Removal of the BOC group with HCl yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].[Cl:19]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:17]([OH:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1
Solvent: CN(C)C=O
Product: Nc1c(O)cc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 22.2 %

Procedure:
2-Amino-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide (3.06 g) and 1.80 g of N-chlorosuccinimide were dissolved in 60 ml of N,N-dimethylformamide, the solution was stirred at 50° C. for 8 hours and at room temperature for 4 hours and the insoluble matter was filtered off. The solvent was evaporated in vacuo, to the resulting residue was added a 1N aqueous solution of sodium hydroxide and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo and the resulting residue was purified by means of a silica gel column chromatography. Ethanol was added to the crudely purified product and the resulting precipitate was collected by filtration and dried in vacuo to give 767 mg of 2-amino-5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide. The mother liquor was concentrated, then ethyl acetate-isopropyl ether was added thereto and the resulting precipitate was collected by filtration and dried in vacuo to give more 942 mg of the above-mentioned compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=3)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>C1COCC1>[ClH:1].[NH2:30][CH2:29][C:25]1[CH:24]=[C:23]([CH2:22][N:13]2[C:14]3[C:19](=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][CH:15]=3)[C:11]([NH:10][S:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:8])=[N:12]2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a cooled, 0° C., solution of 5-chloro-N-[1-[(3-cyanophenyl)methyl]-4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 3) (11.1 g, 24.2 mmol) in THF (150 mL) was added, dropwise maintaining temp below 10° C., 1.0M lithium aluminium hydride solution in ether (60.5 mL, 60.5 mmol), effervescence occurred, and the suspension was stirred at room temperature for one hour. The reaction was quenched by addition of water (7 mL), followed by a 2.0M solution of sodium hydroxide (42.5 mL). After stirring for 30 minutes the solid was removed by filtration and washed with THF. The combined filtrate and washings were treated with 140 g SCX silica. This was filtered and washed with methanol (1 L), and then 10% 2N hydrochloric acid in methanol (2 L). The required fractions were combined and concentrated. The resultant solid was collected by filtration and washed with water. The solid was dried in vacuo to give the title compound (N7916-76-1) (9.3 g, 77%) as a white solid. LCMS (System A) RT=0.85 min, ES+ve m/z 463/465 (M+H)+.