Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH2:73]([O:75][C:76](=[O:80])[CH2:77]CN)[CH3:74]>CN(C)C=O>[CH2:73]([O:75][C:76](=[O:80])[CH2:77][CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:34][CH2:35]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36])[CH3:74]
Reactant: CCOC(=O)CCN
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85 %

Procedure:
To a solution of 0.18 g (0.37 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) in 2 mL N,N-dimethylformamide were added 0.148 g (0.39 mmol) 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.25 mL (1.49 mmol) N,N-diisopropylethylamine. To the light brown solution 0.060 g (0.39 mmol) beta-alanine ethylester hydrochloride (commercially available, CAS RN 4244-84-2) was added and the solution was stirred at room temperature for 3.5 hours. The solution was poured on water and extracted three times with ethyl acetate. The combined organic layers were washed twice with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 0:100) to afford 0.185 g (85%) of the title compound as a light brown foam. MS (ESI): m/z=583.15 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:9])=[C:6]([O:21][CH2:22][C:23](=[O:25])[CH3:24])[CH:5]=1.[H][H].I[CH3:29]>CN(C=O)C>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:9])=[C:6]([O:21][CH:22]([CH3:29])[C:23](=[O:25])[CH3:24])[CH:5]=1
Reactant: [H][H]
Reactant: CI
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC(C)C(C)=O
Reaction time: 1 h

Procedure:
To a stirred suspension of sodium hydride (40 mg of 60%, 1 mmole, washed with n-pentane) in DMF (2 ml) was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-propanon-1-yl)oxybenzamide, prepared in Example 5, (0.349 g, 1 mmole) under nitrogen. The mixture was stirred until evolution of hydrogen subsided, when iodomethane (0.07 ml, 160 mg, 1.1 mmol) was added and stirring continued for 1 hour. The mixture was partitioned between water and methylene chloride, and the organic phase washed with water, dried, concentrated and the residue chromatographed on deactivated silica using methylene chloride (100), methanol (4.5), ammonia (0.5) solvent system. The appropriate fractions were combined to give 160 mg of the title compound as a heavy oil. The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: 6 8.24 (s, superimposed over broad singlet, 2H); 6.08 (s, 1H); 4.70 (q, J=5.4 Hz, 1 H); 4.44 (s, 2H); 3.56 (m, 2H); 2.62 (m, 6H); 2.2 (s, 3H); 1.6 (d, J=5.4 Hz, 3H); 1.04 (t, 6H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11])([CH3:3])[CH3:2].C1COCC1.C([Li])CCC.[Cl-:22].[Cl-].[CH3:24][Zr:25]([CH3:47])(=[SiH2:46])([CH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37]1[CH3:45])[CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[CH3:35]>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O-:11])([CH3:3])[CH3:2].[Cl-:22].[CH3:47][Zr:25]([CH3:24])(=[SiH2:46])([CH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37]1[CH3:45])[CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[CH3:35]
Reactant: Cc1ccc(C(C)C)c(O)c1
Agent: CC1=Cc2ccccc2C1[Zr](C)(C)(=[SiH2])C1C(C)=Cc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(C)C)c([O-])c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
3.2 g (21 mmol) of 2-isopropyl-5-methylphenol in 20 ml of toluene/2 ml of THF were admixed at room temperature with 7.8 ml (21 mmol) of a 20% strength solution of butyllithium in toluene. The mixture was stirred for another 1 hour at 60° C. At room temperature, 5.0 g (10.5 mmol) of dimethylsilanediylbis(2-methylindenyl)zirconium dichloride were added as a solid. The suspension was stirred at 100° C. for 2 hours and subsequently filtered hot through Celite. The filter cake was extracted twice with 25 ml each time of toluene (100° C.). After evaporation of the solvent, the yellow solid which had precipitated was filtered off and dried under reduced pressure. This gave 1.36 g (22%) of dimethylsilanediylbis(2-methylindenyl)zirconium monochloride mono(2-isopropyl-5-methylphenoxide) (4).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C)[CH:27]=[O:28].O.CO>C(OCC)C>[CH2:18]([O:17][CH2:16][C:3]1[CH:4]=[C:5]([O:12][CH2:13][O:14][CH3:15])[CH:6]=[C:7]([O:8][CH2:9][O:10][CH3:11])[C:2]=1[CH:27]=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)C=O
Reactant: COCOc1cc(COCc2ccccc2)c(Br)c(OCOC)c1
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: COCOc1cc(COCc2ccccc2)c(C=O)c(OCOC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
The above-obtained 2-bromo-1-(benzyloxymethyl)-3,5-bis(methoxymethoxy)benzene (1.6 g, 4.3 mmol) was dissolved in diethylether (25 mL) and cooled to −78° C. The obtained solution was added with 1.52 mol/L n-butyllithium-hexane solution (4.0 mL, 6.1 mmol) and stirred at −78° C. for 1 hour. Then, N,N-dimethylformamide (1.0 mL, 13 mmol) was added thereto and stirred at a room temperature for 3 hours. The reaction mixture was added with water and methanol, and then extracted with chloroform 3 times. The organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1 to 5/1 to 3/1) to obtain 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)benzaldehyde (0.99 g, 72%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[C:11]1([N:20]2[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21]2)[C:12]2[N:13]([CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:15][N:16]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[CH3:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([NH:25][C@H:22]2[CH2:23][CH2:24][N:20]([C:11]3[C:12]4[N:13]([CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:15][N:16]=3)[CH2:21]2)=[O:10])=[N:4][CH:3]=1
Reactant: Cc1cnc(C(=O)O)nc1
Reactant: N[C@H]1CCN(c2nccn3cccc23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cnc(C(=O)N[C@H]2CCN(c3nccn4cccc34)C2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
To a solution of 5-methylpyrimidine-2-carboxylic acid (0.03 g, 0.22 mmol, 1 eq) and (S)-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine (0.060 g, 0.22 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.12 mL, 0.86 mmol, 4 eq) and HATU (0.09 g, 0.24 mmol, 1.1 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by HPLC to afford (S)-5-methyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.029 g, 0.09 mmol, 41%). 1H NMR (400 MHz, CD3OD) δ 8.75 (s, 2 H), 7.76 (s, 1 H), 7.71 (d, J=5.5 Hz, 1 H), 7.54 (s, 1 H), 6.91 (s, 1 H), 6.85 (d, J=5.8 Hz, 1 H), 5.00-3.60 (br, 5 H), 2.65-2.30 (br, 2 H), 2.40 (s, 3 H); MS: (ES) m/z calculated for C17H18N6O [M+H]+ 323.2, found 323.
Reaction SMILES: N[C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[CH:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([OH:27])[C:24](O)=[O:25])=[CH:19][CH:18]=1.O.OC1C2N=N[NH:35]C=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:15])([CH3:14])[C:3]([OH:16])=[C:2]([C:21]3[CH2:22][CH2:17][CH:18]=[CH:19][C:20]=3[CH:23]([OH:27])[C:24]([NH2:35])=[O:25])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Oc2ccc(C#N)cc2C(C2=C(C(O)C(N)=O)C=CCC2)=C1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 32.2 %

Procedure:
To a solution of (trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (prepared according to Evans et al., J. Med. Chem., 1983, 26, p. 1582 and J. Med. Chem., 1986, 29, p. 2194) (1.64 g, 7.5 mmol), R(-)-mandelic acid (1.14 g, 7.5 mmol), hydroxybenzotriazole hydrate (1.0 g, 7.5 mmol) in dimethylformamide (15 ml) at 0° C. was added dicyclohexylcarbodiimide (1.55 g, 7.5 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 20 hours and then cooled in an ice bath. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in 5% methanol in chloroform and washed wish 1N sodium hydroxide, 1N hydrochloric acid, brine followed by drying over anhydrous magnesium sulfate. After removing drying agent the solvent was removed in vacuo. The residue was crystallized from ethanol to give the title compound (0.85 g) as a white solid, m.p. 235°-237° C.: [αD ]25 =-94.9° (c=1, MeOH); 1H NMR (DMSO-d6) δ8.45 (d, J=8.0 Hz, 1H), 7.5 (m, 4H), 7.3 (m, 2H), 7.0 (s, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.2 (s, 1H), 5.57 (d, J=5.0 Hz, 1H), 5.0 (s, 1H), 4.76 (t, J=9.0 Hz, 1H), 3.75 (dd, J=4.0 & 5.0 Hz, 1H), 1.40 (s, 3H), 1.15 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:17]=[C:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][C:35](=O)[O:36]C1C=CC([N+]([O-])=O)=CC=1>C(#N)C>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][C:35]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]3[N:17]=[C:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]=[CH:14][CH:13]=3)[CH:7]=2)[N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:36]
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCNc2cc(-c3cccc(C(=O)OC(C)(C)C)n3)ccc21
Solvent: CC#N
Product: CN1CCN(C(=O)Nc2nc3ccccc3s2)c2cc(-c3cccc(C(=O)OC(C)(C)C)n3)ccc21
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A mixture of tert-butyl 6-(1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)picolinate (25G) (36 mg, 0.11 mmol) and 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) (42 mg, 0.13 mmol) in anhydrous acetonitrile (1.0 mL) was heated to reflux for 3 hours, cooled to rt, concentrated under reduced pressure, and the crude material was purified by flash column chromatography on silica gel eluting with a gradient of PE:EtOAc 100:0-70:30, to provide 47 mg (85%) of the desired product tert-butyl 6-(4-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)picolinate (25H): 1H NMR (300 MHz, CDCl3) δ 8.14 (1H, s), 7.88-7.77 (2H, m), 7.74 (2H, d), 7.54 (1H, d), 7.34 (1H, t), 7.22 (1H, t), 6.71 (1H, d), 3.97 (2H, t), 3.49 (2H, t), 3.02 (3H, s), 1.56 (9H, s).
Reaction SMILES: [O:1]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>CN1CCCC1=O.ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([NH:22][C:35](=[O:38])[CH:36]=[CH2:37])[CH:23]=[CH:24][CH:25]=2)=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
Into a 20 mL vial was placed 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline (30.00 mg, 0.08 mmol), N,N-diethylethanamine (0.02 mL, 0.17 mmol) suspended in 1-methylpyrrolidin-2-one (0.35 mL) and dichloromethane (2.00 mL). The resulting mixture was cooled to 0° C. Added acryloyl chloride (0.02 mL, 0.25 mmol). The ice bath was left to melt and the reaction mixture was stirred at rt overnight. The reaction mixture was purified using Biotage column chromatography eluting 0-40% MeOH in EtOAc. Fractions containing the desired product were combined and concentrated. Purified using prep-HPLC eluting 25-55% CH3CN in 0.1% TFA in H2O. Fractions containing the desired product were combined and lyophilized overnight to afford N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide as a white solid (12.00 mg, 35% yield). HPLC purity: 100%, RT=4.235 min. MS: m/z=409 [M+H]+, RT=3.38 min. 1H-NMR (DMSO-d6) δ 10.23 (s, 1H), 8.52 (s, 1H), 8.43 (d, 1H), 7.95 (s, 1H), 7.71 (d, 1H), 7.44-7.33 (m, 4H), 7.19 (d, 2H), 7.13 (t, 1H), 7.09 (d, 2H), 7.02 (d, 2H), 6.80 (d, 1H), 6.45 (dd, 1H), 6.26 (d, 1H), 5.75 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1.[I:14]N1C(=O)CCC1=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[C:6]([O:11][CH3:12])[C:7]([OH:10])=[C:8]([I:14])[CH:9]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: COC(=O)c1cc(I)c(O)c(OC)c1
Reaction time: 1 h
Yield: 113.6 %

Procedure:
To a solution of 4-hydroxy-3-methoxybenzoic acid methyl ester (5.0 g) in tetrahydrofuran (20 mL) was added N-iodosuccinimide (6.17 g) at 0° C., and the mixture was stirred for 1 hour. The precipitated solid was filtered, washed with water, and dried to give the title compound (9.60 g).
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15](S(C)(=O)=O)[N:14]=1)[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([S:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[N:14]=1)[CH3:12]
Reactant: O=C(O)c1cccnc1S
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(Sc2ncccc2C(=O)O)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
4.0 g (0.026 mol) of 2-mercaptonicotinic acid, 5.7 g (0.026 mol) of 4,6-dimethoxyl-2-methylsulfonylpyrimidine and 7.2 g (0.052 mol) of potassium carbonate were weighed, and 70 ml of dimethylformamide was added thereto and the mixture was stirred at 80° C. for 2 hours. The resultant mixture was poured into water, and was washed with 100 ml of ethyl acetate. The aqueous layer was then acidified with 10% HCl aqueous solution to precipitate a crystal. The crystal thus precipitated was filtrated out, and was washed with water and was dried. The crystal was then recrystallized with methanol to obtain 5.3 g of a light-yellowish crystal of the aimed product.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@@H:26]([CH3:37])[CH2:25]3)[CH:18]=2)[CH:14]=[CH:15][CH:16]=1>C1COCC1>[CH3:36][C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][N:24]([CH2:23][C:19]2[CH:18]=[C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][NH:9][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH:12]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:25][C@@H:26]1[CH3:37])=[O:31])([CH3:34])[CH3:35]
Reactant: O=C1CCCC(=O)O1
Reactant: C[C@H]1CN(Cc2cccc(-c3cccc(CN)c3)c2)CCN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C[C@H]1CN(Cc2cccc(-c3cccc(CNC(=O)CCCC(=O)O)c3)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
A mixture of glutaric anhydride (31 mg, 0.27 mmol) and 1,1-dimethylethyl (2S)-4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (100 mg, 0.24 mmol) in THF (5 mL) was stirred at room temperature for about 10 min. It was concentrated. Purification via a CombiFlash (MeOH/DCM) system then afforded the desired product (70 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH3:11].BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:11][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: C1COCCN1
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1ccc(CN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
2-Fluoro-4-nitrotoluene (1.55 g, 10 mmol), N-bromosuccinimide (1.82 g, 10 mmol), and benzoyl peroxide (0.1 g, 0.4 mmol) were dissolved in CCl4 (50 mL). The mixture was heated at reflux, and irradiated with light (100 W bulb) for 4 hours. The reaction mixture was filtered and concentrated. The residue was dissolved in THF (50 mL) and morpholine (1.9 g, 22 mmol) was added to this solution. The mixture was stirred at ambient temperature for 1 hour, and then filtered. The filtrate was evaporated. The title compound was isolated by column chromatography in an amount of 710 mg (30% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]2[C:4](=[C:5]([F:22])[C:6]([F:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([C:12]([C:13](=[CH:25][N:26]([CH3:28])[CH3:27])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19])=[CH:10][C:9]2[C:4](=[C:5]([F:22])[C:6]([F:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CC(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Reaction time: 2 h

Procedure:
A suspension of 26.7 g of ethyl 3-(2-chloro-6,7,8-trifluoro-3-quinolyl-)-3-oxopropionate in 270 cm3 of ethyl acetate and 32 cm3 of N,N-dimethylformamide dimethyl acetal is heated at a temperature close to 75° C., with stirring, for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The dry extract is taken up in 175 cm3 of diisopropyl ether, drained and washed with twice 85 cm3 of the same solvent. 19.32 g of ethyl 2-(2-chloro-6,7,8-trifluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate are obtained in the form of an orange solid melting at 118° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [I:1]Cl.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:27]=[CH:26][C:25]4[C:24]5[C:19](=[CH:20][C:21]([Si](C)(C)C)=[CH:22][CH:23]=5)[C:18]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:17]=4[CH:16]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>CO.ClCCl>[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:27]=[CH:26][C:25]4[C:24]5[C:19](=[CH:20][C:21]([I:1])=[CH:22][CH:23]=5)[C:18]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:17]=4[CH:16]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: ClI
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(-c3ccccc3-c3ccncc3)ccc2-c2ccc([Si](C)(C)C)cc21
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCC1(CCCCCCCC)c2cc(I)ccc2-c2ccc(-c3ccccc3-c3ccncc3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
1.5 ml of an 1.0 M ICl solution in MeOH was slowly added to a solution of 500 mg (0.813 mmol) of 2-(6-p-pyridyl-phenyl)-7-trimethylsilyl-9,9-dioctylfluorene in 5 mL of dichloromethane. The resulting darkred solution was stirred for 2 h at room temperature after which the reaction mixture was quenched with a large excess of a Na2S2O3 in water. The mixture was extracted with water, and the organic fraction was dried using MgSO4 and the solvents were removed under reduced pressure. The product was purified using flash column chromatography (dichloromethane: Rf: 0.36). 450 mg (85%) product was obtained as a highly blue fluorescent, colourless solid material. 1H NMR (250 MHz, CDCl3): δ=8.73 (d, 3J=4.7 Hz, 1H; CH—N), 8.12 (d, 3J=8.5 Hz, 2H; CH—C—C(CH)—N), 7.80-7.73 (mp, 4H, ArH), 7.68 (s, 2H, ArH), 7.65 (d, 3J=5.0 Hz, 2H; CH—CH—N), 7.60 (s, 2H; ArH), 7.48 (d, 1H; 3J=8.4 Hz; ArH), 2.05-1.94 (mp, 4H; CH2—C), 1.05-1.25 (mp, 20H, CH2), 0.81 (t, 3J=6.6 Hz, 6H; CH3), 0.70 (br m, 4H, CH2). 13C{1H} NMR (500 MHz, CDCl3): δ=157.0 (CN), 153.4, 150.9 (C—C—CH2), 149.8 (CH—N), 142.0, 140.4, 140.0, 139.6, 138.2 (ArC), 136.8 (CH—CH—CH—N), 135.9, 132.1 (C—CI), 127.5, 127.3, 126.1, 122.1, 121.5, 121.3, 120.4, 120.1 (CH), 92.6 (CI), 55.5 (C—CH2), 40.2 (C—CH2), 31.7, 29.9, 29.2, 29.1 (CH2), 23.7 (C—CH2—CH2), 22.6 (CH3—CH2), 14.1 (CH3). Exact Mass (IE) m/z: 669.2825 [M]+ (calcd. 669.2832) fractions: 543.6 (m; [M-I]+), 318.4 (m; [M-(C8H17)—I]+). C40H48IN: calcd. C, 71.74; H, 7.22; N, 2.09. found C, 72.34; H, 7.20; N, 2.12.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)=[O:5])#[N:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:1]([CH:3]=[C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[O:5][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])#[N:2]
Reactant: COC(=O)c1ccc(C(=O)CC#N)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=CC#N)OS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 97.2 %

Procedure:
To a mixture of methyl 4-(cyanoacetyl)benzoate (10.29 g), p-toluenesulfonyl chloride (11.58 g) and dichloromethane (110 mL) was added dropwise triethylamine (7.68 g) under ice-cooling. After stirring under ice-cooling for 2.5 hrs, the mixture was diluted with dichloromethane (100 mL), washed with water (150 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:methyl acetate=9:1→1:1) to give the title compound (17.60 g) as a mixture of (E)-form and (Z)-form (6:5).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][C@H:15]1[O:20][C@:16]1([CH3:19])[CH2:17][OH:18]>CO.O.[Ni]>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]([CH3:19])([OH:20])[CH2:17][OH:18]
Reactant: COc1c(C)c(C)c(OC)c(C[C@H]2O[C@]2(C)CO)c1C
Agent: [Ni]
Solvent: O
Solvent: CO
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CO)c1C
Yield: 86.4 %

Procedure:
185 mg of (2R,3R)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2,3-epoxy-2-methylbutanol were dissolved in 5 ml of methanol and the solution was subsequently diluted with 5 ml of water. Thereupon, Raney-nickel was added and the mixture was heated at reflux for 2 hours under hydrogen. After completion of the hydrogen uptake, the mixture was filtered, washed with methanol and methylene chloride and concentrated on a rotary evaporator. Residual water was distilled off azeotropically by the addition of methylene chloride. The oil obtained was recrystallized from hexane/ether and there were obtained 161 mg of 55% (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-butanediol (48% yield; analysis of the acetonide by gas chromatography). Data of the pure substance: m.p. 86°-87° C. [α]D20 +2.55° (c=5.3% in CHCl3).