Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[C:15]([C:27]([F:30])([F:29])[F:28])[CH:14]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].CCN(CC)CC.[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40]>[Cu]I.CN(C=O)C>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[C:15]([C:27]([F:30])([F:28])[F:29])[CH:14]=2)=[O:11])=[CH:3][C:2]=1[C:43]#[C:42][Si:39]([CH3:41])([CH3:40])[CH3:38]
Reactant: Cc1ccc(NC(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#C[Si](C)(C)C
Temperature: 25 °C

Procedure:
The product (1.06 g, 2.0 mmol) obtained from Step 1, CuI (0.19 g, 0.1 mmol), Pd(PPh3)Cl2 (0.35 g, 0.5 mmol) and DMF (10 ml) were added into a 100 ml three-necked flask, and Et3N (0.52 g, 4.0 mmol) and trimethylsilylacetylene (0.98 g, 10 mmol) were added under the protection of an inert gas atmosphere. The mixture was reacted at 80° C. for 16 hours with stirring, and the system was cooled to room temperature, filtered, and extracted with ethyl acetate (50 ml×3) and H2O (50 ml). The organic phases were back-extracted with saturated brine, and the organic phases were combined, dried over anhydrous Na2SO4, and purified by column chromatography, to give a milky white solid.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: Fc1cccc(CBr)c1
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1OCc1cccc(F)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
To a solution of methyl salicylate (1.512 g, 9.93 mmol) in N,N-dimethylformamide (15 ml) were added 3-fluorobenzyl bromide (1.3 ml, 10.6 mmol) and potassium carbonate (1.780 g, 12.88 mmol), and the mixture was stirred at 80° C. for 5 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 2-(3-fluorobenzyloxy)benzoate (1.991 g, 7.65 mmol, yield 77%). This was dissolved in methanol (15 ml), 1N-aqueous sodium hydroxide solution (15 ml) was added at room temperature, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was concentrated under reduced pressure and neutralized with 1N-aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a carboxylic acid compound 2-(3-fluorobenzyloxy)benzoic acid (1.790 g, 7.27 mmol, yield 95%).
Reaction SMILES: Cl[CH2:2][CH2:3]CC(OC(=O)C)CCCCC.ClCCCC(OC(=O)C)(C)CCCCC.[C:30]([O:33][C:34](C)([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:35][CH2:36][CH2:37][N:38]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51]CC)=[O:50])[S:39]([CH3:42])(=[O:41])=[O:40])(=[O:32])[CH3:31]>>[CH2:2]([CH:48]([CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][N:38]([CH2:37]/[CH:36]=[CH:35]/[CH:34]([O:33][C:30](=[O:32])[CH3:31])[CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[S:39]([CH3:42])(=[O:40])=[O:41])[C:49]([OH:51])=[O:50])[CH3:3]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: CCCCCC(C)(CCCN(CCCCCCC(=O)OCC)S(C)(=O)=O)OC(C)=O
Agent: CCCCCC(C)(CCCCl)OC(C)=O
Product: CCCCCC(/C=C/CN(CCCCCC(CC)C(=O)O)S(C)(=O)=O)OC(C)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-4-methylnonane (Example S). The product of Step A is thus ethyl 7-[N-(4-acetoxy-4-methylnonyl)methanesulfonamido]heptanoate. The subsequent step yields 7-[N-(4-hydroxy-4-methylnonyl)methanesulfonamido]heptanoic acid (B).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10](/C(=C\C=C2\N(CCCS([O-])(=O)=O)C3C=CC4C(S([O-])(=O)=O)=CC(S([O-])(=O)=O)=CC=4C=3C\2(C)C)/C=C/C2C(C)(C)C3C4C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=4C=CC=3[N+]=2CCCS([O-])(=O)=O)[CH:11]=[CH:12][CH:13]=1)([OH:3])=[O:2].[Na+:79].[Na+].[Na+].[Na+].[Na+].Br/[C:85](=[CH:110]\[CH:111]=[C:112]1\[N:113]([CH2:127][CH2:128][CH2:129][S:130]([O-:133])(=[O:132])=[O:131])[C:114]2[C:119]([C:120]\1([CH3:122])[CH3:121])=[CH:118][C:117](S([O-])(=O)=O)=[CH:116][CH:115]=2)/[CH:86]=[CH:87]/[C:88]1[C:96]([CH3:98])([CH3:97])[C:95]2[C:90](=[CH:91][CH:92]=[C:93]([S:99]([O-:102])(=[O:101])=[O:100])[CH:94]=2)[N+:89]=1CCCS([O-])(=O)=O.[Na+].[Na+].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12](/[C:85](=[CH:110]\[CH:111]=[C:112]2\[N:113]([CH2:127][CH2:128][CH2:129][S:130]([O-:133])(=[O:132])=[O:131])[C:114]3[C:119]([C:120]\2([CH3:121])[CH3:122])=[CH:118][C:117]([S:130]([O-:133])(=[O:132])=[O:131])=[CH:116][CH:115]=3)/[CH:86]=[CH:87]/[C:88]2[C:96]([CH3:98])([CH3:97])[C:95]3[C:90](=[CH:91][CH:92]=[C:93]([S:99]([O-:102])(=[O:101])=[O:100])[CH:94]=3)[N+:89]=2[CH2:91][CH2:92][CH2:93][S:99]([O-:102])(=[O:101])=[O:100])[CH:11]=[CH:10][CH:9]=1)([OH:3])=[O:2].[Na+:79].[Na+:79].[Na+:79]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Reactant: CC1(C)C(/C=C/C(Br)=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCCCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21

Procedure:
Compound 14 was prepared analogously to compound 8 (Example 8), except that compound 13 was used as starting materials. UV/vis absorption max: λH2O=649 nm, ε=190,000; λMeOH=650 nm, ε=180,000; MS calculated (found) for (M+1)+935.21 (935.3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.C(N(CC)CC)C.[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl>[Br:18][CH2:19][C:20]([O:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)CBr)cc1
Reaction time: 0.17 h
Yield: 92.6 %

Procedure:
To a -78° C. solution of p-methoxybenzyl alcohol (6.91 g, 50 mmol) and triethylamine (6.95 mL, 50 mmol) in anhydrous CH2Cl2 (50 mL) was added a solution of bromoacetyl bromide (10.1 g, 50 mmol) in CH2Cl2 at -78° C. under nitrogen, over a period of 10 min. The cooling bath was removed, and the reaction mixture was stirred for 2 h. The mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to provide 12 g (93% yield) of p-methoxybenzyl bromoacetate as a dark colored oil which was used in the next reaction without purification. A portion was purified by column chromatography on silica gel (elution with 20% ethyl acetate/hexanes) to give a clear, colorless oil. 1H NMR (300 MHz, CDCl3) δ3.79 (s, 3H), 3.83 (s, 2H), 5.12 (s, 2H), 6.87 (m, 2H), and 7.30 (m, 2H); IR (film) 1738 cm-1 ; MS (ESI/NH4OAc) M+NH4+ =276.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[CH:20]=[C:19]([CH:21]([NH:23][CH3:24])[CH3:22])[CH:18]=[CH:17][C:10]=2[O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[F:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>C1COCC1>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:4]=[C:5]([C:9]2[CH:20]=[C:19]([CH:21]([N:23]([CH3:24])[S:43]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)(=[O:45])=[O:44])[CH3:22])[CH:18]=[CH:17][C:10]=2[O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CNC(C)c1ccc(OCC(=O)OC)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(C(C)N(C)S(=O)(=O)c2ccc(F)cc2)cc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of crude methyl 2-(2-(3-trifluoromethylphenyl)-4-(1-(methylamino)ethyl)phenoxy)acetate (18) (100 mg) in 2 mL of THF, was added DIEA (105 mg), and 4-fluorobenzene-1-sulfonyl chloride (87 mg). The reaction mixture was stirred at room temperature for 1 hr and then purified via silica gel chromatography (25% EtOAc/hexane) to give methyl 2-(2-(3-trifluoromethylphenyl)-4-(1-(4-fluoro-N-methylphenylsulfonamido)ethyl)phenoxy)acetate (19) which was carried directly to the next step.
Reaction SMILES: [CH2:1]([C:4]1[CH:21]=[C:20]([CH2:22]O)[CH:19]=[C:18]([CH2:24][CH2:25][CH3:26])[C:5]=1[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH3:3].P(Br)(Br)[Br:28].Br>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:4]1[CH:21]=[C:20]([CH2:22][Br:28])[CH:19]=[C:18]([CH2:24][CH2:25][CH3:26])[C:5]=1[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH3:3]
Reactant: BrP(Br)Br
Reactant: CCCc1cc(CO)cc(CCC)c1Oc1ccccc1CC(=O)OC
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1cc(CBr)cc(CCC)c1Oc1ccccc1CC(=O)OC

Procedure:
To a solution of 2.66.1 g (7.46 mmol) of the product of Step A dissolved in 15 mL of carbon tetrachloride was added 0.709 mL (7.47 mmol) of phosphorous tribromide and the reaction mixture was magnetically stirred at room temperature for 30 min as hydrogen bromide was evolved. The magnetic stir bar was removed, and the reaction mixture was concentrated in vacuo. The residue was redissolved and evaporated from carbon tetrachloride several times to remove most of the hydrogen bromide. Finally, the residue was purified by rapid flash chromatography on a silica gel column eluted with 10% EtOAc-hexane. Combination and evaporation of the purified fractions and drying in vacuo afforded 2.129 (68%) of the title compound which was used directly in the next step without further characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1.Br[CH:27]([CH3:42])[CH2:28][CH2:29][CH2:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:25][O:24][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([NH:1][CH:27]([CH3:42])[CH2:28][CH2:29][CH2:30][N:31]3[C:35](=[O:36])[C:34]4=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]4[C:32]3=[O:41])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=1
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Reactant: COc1cc(N)c2nccc(C=Cc3cccc(C(F)(F)F)c3)c2c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C=Cc3cccc(C(F)(F)F)c3)c2c1
Yield: 78.6 %

Procedure:
A mixture of 8.4 g (0.025 mole) of 8-amino-6-methoxy-4-(3-trifluoromethylstyryl)quinoline, 7.3 g (0.025 mole) of 4-bromo-1-phthalimidopentane and 2.5 g of triethylamine was heated in an oil bath at 130°-135° for 12 hr. The reaction mixture ws dissolved in chloroform and passed through a silica gel column to give 11 g of crude product which was used without further purification. Crystallization from ethanol provided an analytical sample as yellow needles, mp 154°-156°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[C:12](I)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:19]([O:26][CH2:27][C:28]([CH3:61])([CH3:60])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:55])[CH2:38][C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[C:41]([F:54])[CH:40]=2)=[CH:32][C:31]=1[C:56]([F:59])([F:58])[F:57])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12]([C:42]2[CH:43]=[CH:44][C:39]([CH2:38][C:37]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([CH2:29][C:28]([CH3:60])([CH3:61])[CH2:27][O:26][Si:19]([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20])=[C:31]([C:56]([F:59])([F:58])[F:57])[CH:32]=3)=[O:55])=[CH:40][C:41]=2[F:54])=[C:13]([O:15][CH2:16][CH3:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(NC(=O)Cc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)cc1C(F)(F)F
Reactant: CCOc1cc(OCc2ccccc2)ncc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(=O)Nc2ccc(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c(C(F)(F)F)c2)cc1F
Temperature: 110 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a mixture of 2-(benzyloxy)-4-ethoxy-5-iodopyridine (3.2 g, 9.01 mmol) in 1,4-dioxane (60 mL) and water (20 mL) was added N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (6.18 g, 9.91 mmol), Cs2CO3 (5.87 g, 18.02 mmol) and PdCl2(dppf) (0.659 g, 0.901 mmol). The mixture was stirred under nitrogen at 110° C. for 16 h. Then the reaction residue was filtered and the filtrate was concentrated to give the crude product, which was purified by silica column chromatography (PE/EA=5:1). All fractions found to contain product by TLC (PE/EA=5:1, Rf=0.6) were combined and concentrated to yield a light yellow oil of 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-(3-((tert-butyldimethyl silyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (4.2 g, 5.21 mmol, 58% yield): 1H NMR (400 MHz, CD3OD) δ 7.96 (d, J=2.0 Hz, 1H), 7.88 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.47 (d, J=6.0 Hz, 3H), 7.42-7.36 (m, 2H), 7.36-7.30 (m, 2H), 7.27-7.17 (m, 2H), 6.50 (s, 1H), 5.38 (s, 2H), 4.16-4.12 (m, 2H), 3.77 (s, 2H), 3.36 (s, 2H), 2.81 (s, 2H), 1.32 (t, J=6.8 Hz, 3H), 0.97 (s, 9H), 0.85 (s, 6H), 0.12 (s, 6H); ES-LCMS m/z 725.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].[CH3:17]C1C=CC(S(C)(=O)=O)=CC=1.O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[N:7]([CH3:17])[C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nc2cc(Cl)ccc2c(=O)[nH]1
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2cc(Cl)ccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
A mixture of 0.96 g (5.0 mmol) of 7-chloro-2-methyl-4(3H)-quinazolinone and 0.20 g (4.8 mmol) of lithium hydroxide monohydrate in 25 ml of tetrahydrofuran is heated at reflux with stirring for 0.5 h. After cooling to room temperature, 0.89 g (4.8 mmol) of methyl p-toluene sulfonate is added and the reaction mixture heated at reflux for 4 hours. The reaction mixture is neutralized with con. HCl and the solvent removed in vacuo to give a residue. The residue is slurried with 50 ml of water, filtered, washed with 50 ml of 0.5M sodium hydroxide, followed by (3×50 ml) of water. The solid is dried to give 0.73 g (73%) of the desired product, m.p. 162°-165° C. None of the isomeric O-alkylated product is detected by HPLC.
Reaction SMILES: [CH2:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[C:9]([C:17]([OH:19])=[O:18])[CH:8]=[C:7]4[CH:6]=[CH:5][CH:4]3[CH2:3][CH:2]1[C:20]([OH:22])=[O:21]>O.O.O.O.[N+]([O-])([O-])=O.[Zn+2].[N+]([O-])([O-])=O>[CH2:12]1[C:11]2[C:16]3=[C:7]([CH:8]=[C:9]([C:17]([OH:19])=[O:18])[CH:10]=2)[CH2:6][CH2:5][C:4]2=[C:15]3[C:14](=[CH:1][C:2]([C:20]([OH:22])=[O:21])=[CH:3]2)[CH2:13]1
Reactant: O=C(O)c1cc2c3c4c(ccc3c1)CC(C(=O)O)CC4C=C2
Agent: O=[N+]([O-])[O-]
Agent: [Zn+2]
Solvent: O
Product: O=C(O)c1cc2c3c(c1)CCc1cc(C(=O)O)cc(c1-3)CC2
Temperature: 105 °C

Procedure:
Exact amounts of tetrahydropyrene-2,7-dicarboxylic acid, (4,4′-HPDCH2) (0.015 g, 0.05 mmol), and zinc nitrate tetrahydrate, Zn(NO3)2·4H2O, (0.052 g, 0.20 mmol), were dissolved in 10 ml DEF and and placed in a Parr Teflon-lined stainless steel vessel (23 mL). The vessel was sealed and heated at a constant rate (2° C./min) to 105° C. for 20 h and then cooled to room temperature at a rate of 1° C./min. The resultant sample (76%) was filtered and washed with DEF (3×5 mL) yielding IRMOF-11.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]#[N:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C.CCCCCC>ClCCl>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C#N)[nH]n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)c1cc(CN)n(S(=O)(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-tert-butyl-1H-pyrazole-5-carbonitrile (3 g, 20 mmol) in dichloromethane (30 ml, 10 times) TEA (2.44 g (3.36 ml), 24 mmol, 1.2 eq) was added at 0° C. Then phenylsulfonyl chloride (2.84 g (2 ml), 10 mmol, 0.8 eq) was added at 0° C. and the reaction mass was stirred for 12 h at room temperature. Progress of the reaction was monitored by TLC (20% ethyl acetate-hexane, Rf˜0.6). On completion of the reaction, ice water (20 ml) was added to reaction mixture, organic layer was separated and washed with 1N HCl (2×20 ml followed by with water (2×15 ml), Dried the contents over sodium sulfate, concentrated under reduced pressure and the crude product obtained was recrystallized from hexane to yield the required product as an off white solid (4 g, 68%).
Reaction SMILES: [N+:1]([C:4]1[C:10]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O>CO.[Pd]>[N:11]1([C:10]2[CH:9]=[CH:8][CH:7]=[C:5]([NH2:6])[C:4]=2[NH2:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Nc1cccc(N2CCCCC2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(N2CCCCC2)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A mixture of 2-nitro-3-(piperidin-1-yl)aniline (CXXII) (1.64 g, 6.9 mmol, 1 eq) and Pd/C (0.50 g) in MeOH (20 mL) was stirred at room temperature under 30 psi H2 overnight. After the starting material was consumed completely, the mixture was filtered through a Celite pad and the filtrate was concentrated in vacuo to give the 3-(piperidin-1-yl)benzene-1,2-diamine (CXXIII) (1.1 g, 5.75 mmol, 76% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ ppm 1.59 (brs, 2H), 1.73 (quin, J=5.6 Hz, 4H), 2.84 (brs, 4H), 3.50 (brs, 4H), 6.52 (dd, J=6.4 Hz, J=1.6 Hz, 1H), 6.59-6.75 (m, 2H); ESIMS found for C11H17N3 m/z 192 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:11](Cl)(=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:5]([C:4]1[C:3]([CH3:10])=[C:2]([NH:1][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: Cc1c(N)cccc1C#N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(C#N)cccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.6 %

Procedure:
A mixture of 3-amino-2-methylbenzonitrile (4.32 g, 32.7 mmol), benzyl carbonochloridate (7.26 mL, 49.0 mmol), and potassium carbonate (6.78 g, 79.0 mmol) in tetrahydrofuran (280 mL) was stirred at room temperature for 3 days. The insoluble material was removed by filtration, and the filtrate was concentrated under vacuum. The residue was diluted with ethyl acetate (250 mL), washed with 1N HCl solution (60 mL), water (60 mL), and brine (60 mL). The organic solution was dried over anhydrous MgSO4, and the solution was concentrated under vacuum to dryness. The residue was stirred with hexane (100 mL) at room temperature for 1 hr. The insoluble product (6.41 g, 24.07 mmol, 73.6% yield) was collected as a white solid by suction filtration.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]([CH2:19]I)=[CH:17][C:16]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]5)=[N:25][CH:26]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:39])[CH3:2].[CH3:40][O:41][CH2:42][CH2:43][OH:44].[H-].[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]([CH2:19][O:44][CH2:43][CH2:42][O:41][CH3:40])=[CH:17][C:16]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]5)=[N:25][CH:26]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:39])[CH3:2]
Reactant: COCCO
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(CI)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(COCCOC)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
Ethyl 1-[5-[2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-7-(iodomethyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (160 mg, 0.241 mmol) and 2-methoxyethanol (95 μL, 1.21 mmol) were dissolved in THF (10 mL). Sodium hydride (96 mg, 2.41 mmol) was added portion-wise and the mixture stirred under argon at rt for 1 h. The mixture was then diluted with EtOAc (50 mL), carefully quenched with saturated aqueous NH4Cl, washed with water, brine and separated. The organic fraction was dried (Na2SO4), concentrated under reduced pressure and the resulting solid residue purified by flash column chromatography (40 g GraceResolv, silica cartridge) eluting with 50-100% EtOAc/heptane to afford the desired compound (86 mg, 58%) as a colourless resin. MS: 612.16 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][N:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[O:33][C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[CH3:41])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl.Cl.FC1C=CC(C)=C(C=1)OC1N(C2C=CC=CC=2)C2=CN=CC=C2C=1C(N1CCNCC1)=O>>[F:40][C:38]1[CH:37]=[CH:36][C:35]([CH3:41])=[C:34]([CH:39]=1)[O:33][C:17]1[N:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:19]2=[CH:20][N:21]=[C:22]([O:25][CH3:26])[CH:23]=[C:24]2[C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15]
Reactant: COc1cc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3cc(F)ccc3C)n(-c3ccccc3)c2cn1
Agent: Cc1ccc(F)cc1Oc1c(C(=O)N2CCNCC2)c2ccncc2n1-c1ccccc1
Agent: Cl
Product: COc1cc2c(C(=O)N3CCNCC3)c(Oc3cc(F)ccc3C)n(-c3ccccc3)c2cn1
Yield: 98.7 %

Procedure:
The compound of step 6 (27.0 mg, 48.2 μmol) was reacted analogously as described in example 1, step 7. Dissolution of the obtained solid in a small quantity of MOH, addition of hydrochloric acid (0.1 M) and lyophilization overnight yielded 21.9 mg of the title compound in the form of [2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperazin-1-yl-methanone dihydrochloride.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.C(OCC)C.O>CN(C)C=O>[Br:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH2:21][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: Cc1cccc(C(Br)Br)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
0.57 g of potassium phthlimide was suspended in 20 ml of dimethylformamide, and 2.42 g of α,α-dibromo-m-xylene was added. The mixture was stirred overnight at room temperature, and then ethyl ether and water were added. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane / ethyl acetate=10/1] to give 0.52 g of N-(3-bromomethylbenzyl)phthalimide as a white crystalline powder.