Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)=[CH:4][C:3]=1[CH3:20].CO.[H][H]>[Pd].C(O)(=O)C>[NH2:8][C:7]1[CH:6]=[C:5]([N:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16]2)[CH:4]=[C:3]([CH3:20])[C:2]=1[NH2:1]
Reactant: CC(=O)N1CCN(c2cc(C)c(N)c([N+](=O)[O-])c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)N1CCN(c2cc(C)c(N)c(N)c2)CC1
Yield: 99.4 %

Procedure:
To 1-[4-(4-amino-3-methyl-5-nitro-phenyl)-piperazin-1-yl]-ethanone (4.5 g, 16.2 mmol) and 10% palladium on carbon (400 mg) were added methanol (50 mL) and acetic acid (5 mL) under nitrogen. The reaction mixture was stirred under hydrogen atmosphere (hydrogen balloon) for 14 h. The dark solution was filtered through a pad of celite and the filtercake was washed with methanol. Concentration of the filtrate gave the title compound (4.00 g, 100%) which was used for the next step without purification. LCMS (M+H)+ m/z 207 (t=0.41 min.). Procedure for the Preparation of 5-fluoro-3-methyl-2-nitro-aniline:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:29]([NH2:32])[CH2:30][NH2:31]>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:31][CH2:30][CH2:29][NH2:32])[CH:7]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: Fc1cc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)ccn1
Reactant: NCCN
Product: NCCNc1cc(-c2n[nH]c3cnc(-c4cccnc4)cc23)ccn1
Yield: 64 %

Procedure:
Following the procedure of Example 143, 3-(2-fluoropyridin-4-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 1,2-ethylenediamine were reacted and purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 32 mg (64%) of 159. ESI MS m/z 332.1 (M+1). 1H NMR (400 MHz, DMSO): 9.38 (s, 1H), 9.23 (s, 1H), 8.60 (d, J=11.0 Hz, 2H), 8.53 (d, J=7.1 Hz, 1H), 8.10 (s, 1H), 7.54 (s, 1H), 7.25 (d, J=11.9 Hz, 2H), 6.67 (s, 1H), 2.78 (s, 2H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][NH:6][C:7]1[N:12]2[N:13]=[CH:14][C:15]([C:16](O)=[O:17])=[C:11]2[N:10]=[CH:9][C:8]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][NH:6][C:7]1[N:12]2[N:13]=[CH:14][C:15]([C:16]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:17])=[C:11]2[N:10]=[CH:9][C:8]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3cccc(F)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3cccc(F)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-fluorobenzylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.09 g, 0.18 mmol) obtained in step 2 and methanesulfonamide (0.1 g, 1.08 mmol), compound a-6 (0.06 g, 64%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14]Cl)=[C:5]2[O:16][CH3:17].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14][N:22]1[C:18](=[O:28])[C:19]3[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:21]1=[O:23])=[C:5]2[O:16][CH3:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1c(CCl)n(C)c(=O)c2ccc(Cl)cc12
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(CN2C(=O)c3ccccc3C2=O)n(C)c(=O)c2ccc(Cl)cc12
Yield: 51.4 %

Procedure:
A solution of 6-chloro-3-chloromethyl-4-methoxy-2-methyl-1(2H)-isoquinolinone (0.81 g, 3 mmol) and potassium phthalimide (0.83 g, 4.5 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 4 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-{(6-chloro-4methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione (0.59 g, 51.8%) as crystals.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[OH:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][O:23][CH3:24])[CH:4]=[CH:5]2.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][C:31](O)=[O:32].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][C:31](=[O:32])[CH2:30][C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][O:23][CH3:24])[CH:4]=[CH:5]2
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: O=C(O)Cc1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)Cc4cccs4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.1 %

Procedure:
4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (1.98 g, 6 mmol) and thiophene-2-acetic acid (0.853 g, 6 mmol) are dissolved in CH2Cl2 (30 ml) at 25° C. Then N,N'-dicyclohexylcarbodiimide (1.24 g, 6 mmol) and 4-dimethylaminopyridine (0.73 g, 6 mmol) are added to the stirred solution. After the solution has been stirred for a further 14 hours at 25° C., the precipitate is filtered off and washed with CH2Cl2 (20 ml). The combined organic phase is washed with water (2×10 ml), dried (Na2SO4), filtered and evaporated down using a Rotavapor. The residue thus formed is purified by flash chromatography (silica gel; mobile phase: CH2Cl2 :MeOH=9:1). The residue is freed from residual solvent in a high vacuum in order to obtain 4,5α-epoxy-3-methoxymethoxy-17-methyl-6α-((2-thienyl)-acetyloxy)-morphinan-7-ene (2.07 g, 76.1%) as a colourless foam.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[CH:10]=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.C(O[CH:17]=[CH:18][CH:19]=[CH2:20])(=O)C.C([O-])(=O)C.[Na+].O=O>C(O)(=O)C.CN(C)C=O>[CH:17]1[C:10]2[C:11](=[O:12])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7](=[O:8])[C:9]=2[CH:20]=[CH:19][CH:18]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: C=CC=COC(C)=O
Agent: CC(=O)[O-]
Agent: O=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
15.8 parts by weight naphthoquinone and 13.5 parts by weight of 1-acetoxybutadiene in 50 parts by volume of dimethylformamide and 1 part by volume of acetic acid are stirred for 6 hours under nitrogen at 45° - 50° C. 0.4 part by weight of sodium acetate is then added, oxygen is passed in and the batch is stirred for 2 hours at 120° C. After cooling, the anthraquinone which has precipitated is filtered off and washed with dimethylformamide. 18.2 parts by weight (91% of theory) of anthraquinone of melting point 284° C are obtained.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.C(O)CCO.B(F)(F)F.[O:36]1[CH2:40]C[CH2:38][CH2:37]1>>[O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:38][CH2:37][O:36][CH2:40][CH2:2]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: C1CCOC1
Agent: FB(F)F
Solvent: OCCCO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CCOCCO4)CC3)c(F)c2)C(=O)O1
Yield: 51 %

Procedure:
A mixture of (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.275 mmol), 1,3-propanediol (0.330 mmol) and catalytic amount of BF3.etharate in 10 ml tetrahydrofuran was stirred under reflux for 2 hours. The reaction mixture was evaporated to the dryness under vacuum. The residue obtained was purified on the silica gel column chromatography to provide title compound in 51% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-])=O.C(O)C.[H][H]>[Ni].O>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c1OCCO2
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Nc1cc2c(c(C(=O)O)c1)OCCO2
Temperature: 60 °C
Yield: 75.2 %

Procedure:
56 g of 7-nitro-1,4-benzodioxane-5-carboxylic acid, 560 ml of absolute ethanol and Raney nickel were introduced into an autoclave and then hydrogen under a pressure of 65 kg/cm2 was introduced while heating. The mixture was then agitated at 60° C. and treated with a solution of 50 ml of soda lye in 450 ml of water. The solution was filtered and treated with 50 ml of hydrochloric acid. The precipitate was dried off, washed with water and dried. 36.5 g of 7-amino-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 220° C.; yield: 75%).
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([NH:10][CH:11]([CH3:13])[CH3:12])=[N:5][C:6](Cl)=[N:7][CH:8]=1.[CH3:14][S:15][C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C(#N)C>[Br:2][C:3]1[C:4]([NH:10][CH:11]([CH3:13])[CH3:12])=[N:5][C:6]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([S:15][CH3:14])[CH:17]=2)=[N:7][CH:8]=1
Reactant: CSc1cccc(N)c1
Reactant: CC(C)Nc1nc(Cl)ncc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: CSc1cccc(Nc2ncc(Br)c(NC(C)C)n2)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
0.14 ml of a 4 molar solution of hydrogen chloride in dioxane and 0.17 ml of water are added to a solution of 0.152 g (0.61 mmol) of (5-bromo-2-chloropyrimidin-4-yl)-isopropylamine and 0.077 g (0.55 mmol) of 3-methylsulphanylphenylamine in 2 ml of acetonitrile, and the mixture is then stirred at 50° C. for 24 hours. After cooling, the mixture is added to saturated sodium bicarbonate solution. It is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate. Removal of the solvent and recrystallization of the residue from ethyl acetate/hexane 9/1 result in 0.17 g (79% of theory) of the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[CH:20][C:19]3[C:10](=[C:11]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:12]4[C:17]([C:18]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:34]1[C:42]2[C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[O:39][C:38]=2[C:37]([C:47]2[CH:48]=[CH:49][C:50]3[NH:51][C:52]4[C:57]([C:58]=3[CH:59]=2)=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:36][CH:35]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CCCCCC.C1(C)C=CC=CC=1>[CH:34]1[C:42]2[C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[O:39][C:38]=2[C:37]([C:47]2[CH:48]=[CH:49][C:50]3[N:51]([C:6]4[CH:7]=[CH:2][CH:3]=[C:4]([C:8]5[CH:21]=[CH:20][C:19]6[C:10](=[C:11]([C:28]7[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=7)[C:12]7[C:17]([C:18]=6[C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)=[CH:16][CH:15]=[CH:14][CH:13]=7)[CH:9]=5)[CH:5]=4)[C:52]4[C:57]([C:58]=3[CH:59]=2)=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:36][CH:35]=1
Reactant: Brc1cccc(-c2ccc3c(-c4ccccc4)c4ccccc4c(-c4ccccc4)c3c2)c1
Reactant: c1ccc2c(c1)[nH]c1ccc(-c3cccc4c3oc3ccccc34)cc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: c1ccc(-c2c3ccccc3c(-c3ccccc3)c3cc(-c4cccc(-n5c6ccccc6c6cc(-c7cccc8c7oc7ccccc78)ccc65)c4)ccc23)cc1
Yield: 58.7 %

Procedure:
In a 100-mL three-neck flask were put 1.0 g (2.1 mmol) of 2-(3-bromophenyl)-9,10-diphenylanthracene, 0.69 g (2.1 mmol) of 3-(dibenzofuran-4-yl)-9H-carbazole, and 0.59 g (6.2 mmol) of sodium tert-butoxide. After the air in the flask was replaced with nitrogen, to this mixture were added 20 mL of toluene and 0.2 mL of tri(tert-butyl)phosphine (a 10 wt % hexane solution). This mixture was degassed by being stirred while the pressure was reduced. After the degassing, 59 mg (0.10 mmol) of bis(dibenzylideneacetone)palladium(0) was added to this mixture. This mixture was stirred at 110° C. for 5 hours under a nitrogen stream. After the stirring, the obtained mixture was suction-filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). The filtrate was concentrated to give a yellow solid. The obtained solid was recrystallized from toluene, and the obtained crystal was purified by high performance liquid column chromatography (abbreviation: HPLC) (chloroform as the developing solvent). The obtained fraction was concentrated to give 0.91 g of a pale yellow solid in 60% yield. The synthesis scheme of Step 2 is illustrated in (b-17).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CCCCNCCCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
To a solution of 6-bromopicolinic acid (Aldrich, 404 mg, 2.00 mmol) in DMF (3.0 mL) were added dibutylamine (Aldrich, 258 mg, 2.00 mmol), HATU (760 mg, 2.00 mmol) and DIEA (1.1 mL, 6.00 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched by adding sat. aq. NH4Cl solution. The mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, gradient from 0 to 20% EtOAc/DCM to give a light brown oil (450 mg, 72%). 1H NMR (CDCl3) δ 7.67-7.57 (m, 2H), 7.51 (dd, J=7.5, 1.3 Hz, 1H), 3.53-3.42 (m, 2H), 3.36-3.27 (m, 2H), 1.72-1.56 (m, 4H), 1.46-1.33 (m, 2H), 1.27-1.15 (m, 2H), 0.97 (t, J=7.4 Hz, 3H), 0.85 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 313.2 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C@@H:6]2[CH2:8][C@H:7]2[CH:9]=O)[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.[CH3:15][NH:16][CH3:17].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.Cl>[S:1]1[CH:5]=[C:4]([CH:6]2[CH2:8][CH:7]2[CH2:9][N:16]([CH3:17])[CH3:15])[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2
Reactant: CNC
Reactant: O=C[C@@H]1C[C@H]1c1csc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)CC1CC1c1csc2ccccc12
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Trans-2-benzo[b]thiophen-3-yl-cyclopropanecarbaldehyde (202 mg, 1.0 mmol) was dissolved in 10 mL ethanol. To this solution was added a 2.0 M solution of dimethylamine in THF (5.0 mL, 10.0 mmol). After stirring for 15 min, sodium triacetoxyborohydride (850 mg, 4.0 mmol) was added and the reaction continued for 1 h. The reaction was diluted with 10 mL 0.1 N HCl, then solid sodium bicarbonate was added in portions to adjust pH to 7. The mixture was extracted with ethyl acetate (2×20 mL), and the organic extracts were pooled, washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by preparative reverse phase high-performance liquid chromatography afforded (2-benzo[b]thiophen-3-yl-cyclopropylmethyl)-dimethyl-amine (246 mg, 71%) as an oily trifluoroacetic acid salt. 1H NMR (500 MHz, d4-MeOH) 7.94 (1H, d, J=7.94 Hz), 7.86 (1H, d, J=7.93 Hz), 7.42 (1H, t, J=7.94), 7.37 (1H, t, J=7.94), 7.21 (1H, s), 3.44 (1H, dd, J=13.12, 6.71 Hz), 3.22 (1H, dd, J=13.12, 8.24 Hz), 2.97 (6H, s), 2.28 (1H, p, J=4.6 Hz), 1.56 (1H, m), 1.20 (2H, m). LC-MS: 1.10 min; 232.2 (MH)+.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]([NH:17][C:18]([C:20]1[S:21][C:22]([C:27](=[O:39])[NH:28][CH2:29][C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)=[CH:23][C:24]=1[C:25]#[N:26])=[O:19])[CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:10]([OH:15])[CH:9]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[C:25]([C:24]1[CH:23]=[C:22]([C:27](=[O:39])[NH:28][CH2:29][C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)[S:21][C:20]=1[C:18]([NH:17][C@@H:4]([CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([OH:14])[CH:13]=1)[C:3]([OH:40])=[O:2])=[O:19])#[N:26]
Reactant: COC(=O)[C@H](CNC(=O)c1cc(O)cc(O)c1)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cc(O)cc(O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-2-({3-Cyano-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-3-(3,5-dihydroxy-benzoylamino)-propionic acid methyl ester (124.1 mg, 0.22 mmol) in THF (10 mL) was added a solution of lithium hydroxide monohydrate (65 mg, 1.54 mmol) in water (12 mL). The mixture was then stirred at room temperature 1.5 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to afford to pure product, 78.6 mg (65%). MS m/e 549.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:12]=1.Br[C:27]1[CH:28]=[C:29]([OH:34])[CH:30]=[C:31](Br)[CH:32]=1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:27]2[CH:28]=[C:29]([OH:34])[CH:30]=[C:31]([C:14]3[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][CH2:8][O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:16][CH:15]=3)[CH:32]=2)=[CH:15][CH:16]=1
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: COCCOCOCCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COCCOCOCCCc1ccc(-c2cc(O)cc(-c3ccc(CCCOCOCCOC)cc3)c2)cc1

Procedure:
In analogy to the synthesis described in 8.1, 2-{4-[3-(2-methoxyethoxymethoxy)-propyl]-phenyl}-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 3,5-dibromophenol are reacted to give 4,4″-bis-[3-(2-methoxyethoxymethoxy)-propyl]-5′-hydroxy-[1,1′;3′,1″]terphenyl as colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[C:9]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C)C=O>[Si:30]([O:24][CH:21]1[CH2:20][CH2:19][N:18]([C:9]2[C:10]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])=[CH:11][C:2]([Cl:1])=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)[CH2:23][CH2:22]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1N1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a mixture of 5-chloro-8-(4-hydroxypiperidin-1-yl)-N-methoxy-N-methylquinoline-7-carboxamide (372 mg, 1.06 mmol) and 1H-imidazole (0.362 g, 5.32 mmol) in N,N-dimethylformamide (2 mL) was added tert-butyldimethylsilyl chloride (0.240 g, 1.60 mmol). The reaction was stirred at room temperature overnight, then quenched with sat. sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 40% ethyl acetate in hexane, to give the desired product (0.312 g, 63%). LCMS calculated for C23H35ClN3O3Si (M+H)+: m/z=464.2; Found: 464.2.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].[C:11]1([C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N+]=[N-])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[CH:17]([O:8][C:5]1[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=c1cc(CO)occ1O
Solvent: CCO
Product: O=c1cc(CO)occ1OC(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 56.8 %

Procedure:
14.2 g (0.1 mol) of kojic acid was added to ethanol (400 ml), and heated to 60° C. and dissolved. After cooling the solution to room temperature, 29.1 g (0.15 mol) of diphenyldiazomethane was added thereto, and the mixture was reacted at room temperature for 18 hours under stirring. The reaction solution was concentrated to dryness, and benzene (300 ml) was added thereto. Then, insolubles were removed by filtration. To the filtrate, water (300 ml) was added, and the precipitates thereby formed were collected by filtration, and washed with benzene to obtain 17.5 g (yield: 56.8%) of the above identified compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[N:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])(=[O:16])=[O:15]>C(#N)C>[CH3:10][N:8]([CH3:9])[C:6]1[N:5]=[C:4]([O:11][CH3:12])[N:3]=[C:2]([NH:1][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[S:14]([CH3:13])(=[O:16])=[O:15])(=[O:25])=[O:24])=[O:28])[N:7]=1
Reactant: COc1nc(N)nc(N(C)C)n1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2S(C)(=O)=O)nc(N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-amino-4-dimethylamino-6-methoxy-1,3,5-triazine (1.02 g, 6.00 mmol) in dry acetonitrile (30 ml) was added 2-methylsulfonylbenzenesulfonyl isocyanate (1.50 g, 6.00 mmol). After stirring at room temperature overnight, the reaction mixture was filtered and the solid washed with acetonitrile to give the product as a white powder with a melting point of 192°-195° C.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[Br:53][CH2:54][C:55](Br)=[O:56].C(N(CC)CC)C>C(Cl)Cl>[C:8]([O:27][CH2:28][CH2:29][N:30]([C:55](=[O:56])[CH2:54][Br:53])[CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCNCCOC(=O)CCCCCCC/C=C\CCCCCCCC
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Synthesis of (Z)-azanediylbis(ethane-2,1-diyl) dioleate TFA salt previously described. (Z)-azanediylbis(ethane-2,1-diyl) dioleate TFA salt (1.50 g, 2.34 mmol) was dissolved in DCM (20 mL) and placed in an ice-bath. Bromoacetyl bromide (214 uL, 2.46 mmol) was added followed by triethylamine (685 uL, 4.91 mmol). The ice-bath was removed and the reaction was allowed to stir overnight at room temperature under inert gas, then diluted with DCM to 100 mL, and washed with a 1M HCl (75 mL), H2O (75 mL), saturated NaHCO3 solution (75 mL) and saturated brine solution (75 mL). All aqueous washes were back extracted with DCM (25 mL). Dried organics with MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography with ethyl acetate yielded (Z)-((2-bromoacetyl)azanediyl)bis(ethane-2,1-diyl) dioleate (1.22 g).