Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[C:5]([Cl:12])[C:4]=1[CH:13]1[CH2:20][N:16]2[CH2:17][CH2:18][N:19]=[C:15]2[CH2:14]1.[H][H]>O.[Ni]>[BrH:1].[NH2:9][C:8]1[C:3]([Cl:2])=[C:4]([CH:13]2[CH2:20][N:16]3[CH2:17][CH2:18][N:19]=[C:15]3[CH2:14]2)[C:5]([Cl:12])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C2CC3=NCCN3C2)c1Cl
Agent: [Ni]
Agent: Br
Solvent: O
Product: Nc1ccc(Cl)c(C2CC3=NCCN3C2)c1Cl

Procedure:
A solution of 6-(2,6-dichloro-3-nitrophenyl)-2,3,6,7-tetrahydro-5H-pyrrolo[1,2-a]imidazole hydrobromide (2.3 g.) in water (70 ml.) is shaken with hydrogen in the presence of a Raney nickel catalyst (0.5 g.) at laboratory temperature and atmospheric pressure until uptake of hydrogen ceases. The mixture is filtered, the filtrate is evaporated to dryness and the residue is dissolved in hot ethanol (200 ml.). The solution is concentrated to 20 ml. by distillation and then cooled and filtered. There is thus obtained as solid residue 6-(3-amino-2,6-dichlorophenyl)-2,3,6,7-tetrahydro-5H-pyrrolo-[1,2-a]imidazole hydrobromide, m.p. 275°-277° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.Cl.[NH2:14][CH:15]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:16]1=[O:17].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:8])[N:14]([CH:15]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:16]1=[O:17])[C:9]2=[O:10]
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3ccc(Br)cc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A mixture of 4-bromophthalic anhydride (10.0 g, 44.1 mmol), rac-α-aminoglutarimide hydrochloride (7.25 g, 44.0 mmol) and sodium acetate (3.61 g, 44.0 mmol) in acetic acid (150 mL) was heated to reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under vacuum. The residue was stirred in water (170 mL) for 3 hours, and the resulting solid was filtered, washed with additional water (80 mL), and dried under vacuum, to afford 13.8 g of 5-bromo-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione, in 93% yield; 1H NMR (DMSO-d6) δ 2.03-2.10 (m, 1H), 2.43-2.63 (m, 2H), 2.82-2.97 (m, 1H), 5.17 (dd, J=12.8 Hz, J=5.3 Hz, 1H), 7.85-7.88 (d, J=7.9 Hz, 1H), 8.10 (dd, J=7.9 Hz, J=1.7 Hz, 1H), 8.16 (d, J=1.7 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.9, 30.9, 49.2, 125.3, 126.4, 128.5, 130.1, 133.2, 137.6, 165.9, 166.4, 169.7, 172.7; Anal. Calcd for C13H9N2O4Br: C, 46.32; H, 2.69; N, 8.31. Found: C, 46.23; H, 2.47; N, 8.41.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:26]([O:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:26]([O:30][C:31]([NH:33][CH2:34][C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 18 from (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone, N-tert.butoxycarbonyl-glycine, TBTU, HOBt and N-methylmorpholine in DMF.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:13](=[O:14])[NH:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1

Procedure:
Methyl-3,4-diaminobenzoate (1.251 g, 7.5 mmol, Lancaster) was reacted with 1,1′-carbonyldiimidazole (2.128 g, 13.1 mmol, Aldrich) under the conditions of Example 1b to give the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 193 (M+1).
Reaction SMILES: [S:1]1[C:5]2[NH:6][CH:7]=[CH:8][C:9](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)CC>[N+:11]([C:8]1[C:9](=[O:10])[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[NH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=c1cc[nH]c2sccc12
Solvent: CCC(=O)O
Product: O=c1c([N+](=O)[O-])c[nH]c2sccc12
Temperature: 130 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of 3.4 g of thieno[2,3-b]pyridin-4(7H)-one 5 in 105 ml of propionic acid is added 2.79 g of concentrated nitric acid (d=1.38) at 100° C., and then the mixture is stirred at 130° C. (bath temperature) for 1 hour. After cooling the reaction mixture, the resulting precipitate is collected by filtration and washed successively with water, methanol and acetone to afford 3.4 g (77%) of Compound 6 as pale yellow crytals melting at 288°-291° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](S(C)(=O)=O)=[N:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]2)=[N:6][CH:7]=1.[OH:21][C:22]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[C:3]([O:21][C:22]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][CH:23]=2)=[N:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(-n2cc(C(F)(F)F)cn2)nc1S(C)(=O)=O
Reactant: Oc1csc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(-n2cc(C(F)(F)F)cn2)nc1Oc1csc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 48.8 %

Procedure:
A mixture of 0.8 g (2.6 mmol) of 5-methyl-4-methylsulfonyl-2-(4-trifluoromethyl-1H-1-pyrazolyl)pyrimidine, 0.44 g (2.6 mmol) of 3-hydroxy-5-trifluoromethylthiophene and 0.72 g (5.2 mmol) of K2CO3 in 10 ml of DMF is stirred at 60° C. for 6 h and then at RT for 48 h. It is subsequently poured into 20 ml of water and extracted with four times 15 ml of CH2Cl2. The combined organic phase is dried over Na2SO4, filtered and concentrated. Chromatographic purification on silica gel with heptane/ethyl acetate (3:7) as eluent gives 0.5 g of 5-methyl-2-(4-trifluoromethyl-1H-1-pyrazolyl)-4-(5-trifluoromethyl-3-thienyloxy)pyrimidine as colorless crystals.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([NH2:14])=[N:8][NH:9]2.CC(N(CC1C=CC(CN2C3C(=C(OC)C=CC=3)C(NS(C3SC(Cl)=CC=3)(=O)=O)=N2)=CC=1)C(=O)[O-])(C)C.Cl[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[C:56]([O:62][CH3:63])[CH:55]=1>CS(C)=O.O>[CH3:63][O:62][C:56]1[CH:55]=[C:54]([CH2:53][N:9]2[C:10]3[C:6](=[C:5]([O:4][CH3:3])[CH:13]=[CH:12][CH:11]=3)[C:7]([NH2:14])=[N:8]2)[CH:59]=[CH:58][C:57]=1[O:60][CH3:61]
Reactant: COc1cccc2[nH]nc(N)c12
Reactant: COc1ccc(CCl)cc1OC
Agent: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(CN(C(=O)[O-])C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(N)c3c(OC)cccc32)cc1OC
Reaction time: 0.25 h
Yield: 84 %

Procedure:
Powdered KOH (0.494 g, 8.80 mmol) was dissolved in DMSO (20 mL) under nitrogen and 4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (0.653 g, 4 mmol) was added. The mixture was stirred for 15 min to give a deep red solution. 4-(Chloromethyl)-1,2-bis(methyloxy)benzene (0.896 g, 4.80 mmol) was added in one portion and the mixture was stirred for 2 h. The mixture was added to water (150 mL) and extracted with dichloromethane (3×50 mL). The dried (Na2SO4) extract was evaporated and the residue was triturated with diethyl ether (3×3 mL) to give the title compound (1.05 g, 84%) as an orange solid. LCMS (System B) RT=2.22 min, ES+ve m/z 314 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[C:18]1([Li])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([OH:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(O)c3ccccc3)ccc2[nH]1
Reaction time: 1 h

Procedure:
To a stirred solution of 2.00 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 100 ml of tetrahydrofuran, cooled at 0° C., is added 13.0 ml of 2.0 M phenyllithium and stirring continued for 1 hour. The cooling is removed and the reaction allowed to reach room temperature followed by an additional 30 minutes at room temperature. The reaction is diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer is dried, evaporated to a residue, which is purified by chromatography on silica gel by elution with 0.25:100 methanol-chloroform to give 0.932 g of the desired product. CI MASS SPEC 309(MH
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](O)=[O:8].C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C)C=O>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([Cl:14])=[O:8]
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)C(C(=O)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.50 g, 3.5 mmol) in 18 mL of methylene chloride at 0° C. was added oxalyl chloride (0.61 mL, 7.0 mmol) and a catalytic amount of dimethylformamide (2 drops). The solution was stirred at ambient temperature for 1 hour, and then concentrated under reduced pressure to provide 0.56 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN(C=O)C>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:20][CH2:21][O:22][CH3:23])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COCCBr
Reactant: COc1cc(C=O)c(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(F)c(C=O)cc1OC
Reaction time: 86 h

Procedure:
2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (0.500 g, 2.94 mmol) was dissolved in DMF (2.6 mL) containing Cs2CO3 (2.88 g, 8.82 mmol). 1-Bromo-2-methoxy-ethane (1.23 g, 828 μL, 8.82 mmol) was added and the reaction mixture was allowed to stir for 86 h. The reaction mixture was filtered and the filtrate was evaporated to dryness to give 2-fluoro-5-methoxy-4-(2-methoxyethoxy)benzaldehyde. ESI-MS m/z calc. 228.1. found 229.0 (M+1)+. Retention time: 1.14 minutes (3 min run).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].F[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])=[N:12][CH:13]=1
Reactant: N#Cc1cccc(O)c1
Reactant: Cc1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2cccc(C#N)c2)nc1
Temperature: 150 °C
Yield: 35.9 %

Procedure:
A mixture of 3-hydroxy-benzonitrile (500 mg, 4.17 mmol), 2-fluoro-5-methyl pyridine (467 mg, 4.17 mmol) and K2CO3 (150 mg) in N,N-dimethylformamide (5 mL) was heated at 150° C. overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographered using hexane/ethyl acetate (2:1) to give the title compound (315 mg, 36%). MS (DCI/NH3) m/z 211 (M+1)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H) 7.02 (d, J=8.59 Hz, 1H) 7.45 (ddd, J=8.29, 1.53, 0.92 Hz, 1H) 7.61 (m, 3H) 7.71 (ddd, J=8.29, 2.46, 0.61 Hz, 1H) 7.99 (dt, J=2.45, 0.61 Hz, 1H).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25].CCN(C(C)C)C(C)C.[F:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][C@@H:37]([F:36])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25]
Reactant: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)CCC1(F)F
Reactant: F[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](F)C4)ccc23)CCC1(F)F

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-fluoro-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.66 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.56 (m, 1H), 1.27-1.32 (m, 1H), 1.00 (d, 3H). m/z: 456 [M+H]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([CH:11]([CH2:14][CH3:15])[CH2:12]O)[CH3:10]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:12][CH:11]([CH2:14][CH3:15])[CH2:9][CH3:10])[CH:3]=1
Reactant: CCC(CC)CO
Reactant: Oc1cccc(Br)c1
Product: CCC(CC)COc1cccc(Br)c1

Procedure:
Coupling of 3-bromophenol (17) (5.0 g, 28.9 mmol) with 2-ethylbutan-1-ol (3.25 g, 31.79 mmol) was conducted following the procedure given for Example 6. The reaction mixture was concentrated under reduced pressure then triturated with diethyl ether. The suspension was filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (100% hexanes) gave 1-bromo-3-(2-ethylbutoxy)benzene a clear liquid. Yield (5.04 g, 62%): 1H NMR (400 MHz, DMSO-d6) δ 7.20 (t, J=8.0 Hz, 1H), 7.11 (t, J=2.2 Hz, 1H), 7.07 (dd, J=8.0, 2.0 Hz, 1H), 6.92 (dd, J=8.4, 2.6 Hz, 1H), 3.84 (d, J=5.6 Hz, 2H), 1.61-1.53 (m, 1H), 1.46-1.30 (m, 4H), 0.86 (t, J=7.4 Hz, 6H).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:23])[CH2:21][CH2:20][NH:19][CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>>[ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:23])[CH2:21][CH2:20][N:19]([CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: BrCCOc1ccccc1
Reactant: CC1CNCCC1(F)c1cccc(OCc2ccccc2)c1
Agent: Cl
Product: CC1CN(CCOc2ccccc2)CCC1(F)c1cccc(OCc2ccccc2)c1

Procedure:
This material was prepared by the alkylation of 4-(3-benzyloxyphenyl)-4-fluoro-3-methylpiperidine hydrochloride with 1-bromo-2-phenoxyethane and subsequent salt formation with methanolic hydrogen chloride as described in Step 3 of Example 1 in 67% overall yield.
Reaction SMILES: [CH2:1]([C:3]([CH:10]([CH3:28])[C:11](=[O:27])[C:12]1[CH:26]=[CH:25][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:18][C:14]=2[CH:13]=1)(C(O)=O)[C:4]([OH:6])=[O:5])[CH3:2].C(O)COCCO.COC>O>[CH2:1]([CH:3]([CH:10]([CH3:28])[C:11](=[O:27])[C:12]1[CH:26]=[CH:25][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:18][C:14]=2[CH:13]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCC(C(=O)O)(C(=O)O)C(C)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: COC
Solvent: O
Solvent: OCCOCCO
Product: CCC(C(=O)O)C(C)C(=O)c1ccc2nc(-c3ccccc3)oc2c1

Procedure:
200 mg (524 μmol) 2-ethyl-2-[1-methyl-2-oxo-2-(2-phenyl-benzoxazol-6-yl)-ethyl]-malonic acid are heated together with 5 ml diethyleneglycol-dimethylether for 1 h at 140° C. in the microwave. The solv. is largely removed i.V., the residue is mixed with a little water and freeze-dried.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:36]([NH:35][CH2:33][CH3:34])=[O:37])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCN=C=O
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCNC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.44 g, 2.91 mmol) was added to a stirred suspension of 3-[4-(aminomethyl)-1-oxoisoindolin-2-yl]piperidine-2,6-dione hydrochloride (0.6 g, 1.94 mmol) in acetonitrile (50 mL). After stirring for 30 min, ethyl isocyanate (0.21 g, 2.91 mmol) was added. The mixture was stirred at room temperature for 17 hours. Solvent was removed and the residue was stirred with methylene chloride (70 mL) to give N-{[2-(2,6-dioxo(3-piperidyl))-1-oxoisoindolin-4-yl]methyl}(ethylamino)carboxamide (0.28 g, 42%) as a white solid: mp 341-343° C.; 1H NMR DMSO-d6) δ 11.02 (s, 1H), 7.62-7.47 (m, 3H), 6.40 (t, J=5.9 Hz, 1H), 5.95 (t, J=5.6 Hz, 1H), 5.18-5.10 (dd, J=5.3 and 13.3 Hz, 1H), 4.52-4.30 (dd, J=17.3 and 37.7 Hz, 2H), 4.28 (d, J=5.9 Hz, 2H), 3.04 (q, J=7.2 Hz, 2H), 3.01-2.86 (m, 1H), 2.65-2.34 (m, 2H0, 2.04-1.99 (m, 1H), 0.98 (t, J=7.2 Ha, 3H), 13C NMR (DMSO-d6) δ 172.82, 170.97, 168.10, 157.86, 139.78, 136.24, 131.55, 130.25, 128.16, 121.32, 51.51, 46.13, 34.14, 31.16, 22.59, 15.67; Anal. Calcd for C17H20N4O4: C, 59.29; H, 5.85; N, 16.27. Found: C, 58.98; H, 5.85; N, 16.89.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([OH:33])(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[CH2:34]([O:41][CH2:42][C@H:43](O)[CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(Cl)(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:34]([O:41][CH2:42][C@H:43]([O:32][C:16](=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCCCCC/C=C\CCCCCCCCOC[C@@H](O)COCc1ccccc1
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCOC[C@H](COCc1ccccc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 4 mL solution of DCC (111 mg, 0.54 mmol), DMAP (3 mg, 0.02 mmol) and palmitic acid (86 mg, 0.34 mmol) in CH2Cl2 was cooled to 0° C. A solution of 3-O-benzyl-1-O-oleyl-sn-glycerol (100 mg, 0.228 mmol) in CH2Cl2 (2 mL) was added to it in a drop-wise manner and stirred for 12 h at rt. The mixture was filtered over Celite, washed with saturated aqueous sodium bicarbonate solution and brine, dried on anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography using silica gel (hexane:EtOAc=15:1, Rf=0.35) to get the product (154 mg, quantitative) as colorless oil. [α]D28+5° (c=2.0, CHCl3); IR (CHCl3) cm−1 2924, 2854, 1742, 1651, 1460, 1369, 1241, 1164, 1109, 1028, 733, 698 cm−1; 1H NMR (600 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H, CH3), 1.22-1.38 (m, 44H, CH2), 1.52 (dt, J=7.2, 14.4 Hz, 4H, CH2), 1.94 (dd, J=6.6, 12.6 Hz, 4H, CH2), 2.20 (t, J=7.8 Hz, 2H, CH2), 2.24 (t, J=7.8 Hz, 2H, CH2), 3.51 (ddd, J=5.0, 10.2, 15.6 Hz, 2H, CH2OBn), 4.11 (dd, J=5.4, 12.0 Hz, 1H, CH2OAcyl), 4.27 (dd, J=3.6, 12.0 Hz, 1H, CH2OAcyl), 4.44, 4.48 (AB q, J=12.0 Hz, 2H, PhCH2), 4.06 (dt, J=4.2, 9.0 Hz, 1H, CH), 5.35 (ddd, J=6.0, 11.4, 15.6 Hz, 2H, CH═CH 7.20-7.32 (m, 5H, ArH); 13C NMR (150 MHz, CDCl3) δ 14.1, 22.65, 22.66, 24.8, 24.9, 27.1, 27.2, 29.06, 29.09, 29.16, 29.27, 29.29, 29.33, 29.46, 29.50, 29.61, 29.63, 29.67, 29.74, 31.88, 31.90, 34.1, 34.3, 62.6, 68.2, 70.0, 73.3, 127.6, 127.7, 128.4, 129.7, 130.0, 137.7, 173.0, 173.3; EMSI calc'd for C44H76NaO5 [M+Na]+ 707.56. found: 707.50.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[N:13]3[CH:14]=[C:15](I)[C:16]([C:18]#[N:19])=[CH:17][C:12]3=[N:11][C:10]=2[C:21]([F:24])([F:23])[F:22])[CH2:4][CH2:3]1.[CH3:26][C:27]1(C)C(C)(C)OB(C=C)O1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[N:13]3[CH:14]=[C:15]([CH:26]=[CH2:27])[C:16]([C:18]#[N:19])=[CH:17][C:12]3=[N:11][C:10]=2[C:21]([F:24])([F:23])[F:22])[CH2:4][CH2:3]1
Reactant: N#Cc1cc2nc(C(F)(F)F)c(CC3CCC(F)(F)CC3)n2cc1I
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: C=Cc1cn2c(CC3CCC(F)(F)CC3)c(C(F)(F)F)nc2cc1C#N
Temperature: 60 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
3-(4,4-Difluorocyclohexylmethyl)-6-iodo-2-trifluoromethylimidazo[1,2-a]pyridine-7-carbonitrile (20.0 mg, 0.0430 mmol) obtained in step 2 was dissolved in 1,2-dichloromethane (0.60 mL), and the solution was stirred at 60° C. for 1 hour after adding 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (24.0 mg, 0.153 mmol), tetrakis(triphenylphosphine)palladium(0) (4.93 mg, 0.00426 mmol), and water (0.2 mL). The reaction mixture was filtered through Celite (registered trademark), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→50/50) to give 3-(4,4-difluorocyclohexylmethyl)-2-trifluoromethyl-6-vinylimidazo[1,2-a]pyridine-7-carbonitrile (11.0 mg, yield 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7](CC2C=CC(C)=CC=2)[C:8]2[C:16]3[S:15][C:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:13][C:12]=3[C:11]([O:26][CH3:27])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH2:42][C:43]([Cl:46])([Cl:45])[Cl:44])=[O:40]>C(#N)C>[Cl:44][C:43]([Cl:46])([Cl:45])[CH2:42][O:41][C:39](=[O:40])[N:7]([C:8]1[C:16]2[S:15][C:14]([NH:17][C:18](=[O:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:13][C:12]=2[C:11]([O:26][CH3:27])=[CH:10][CH:9]=1)[CH2:6][C:5]1[CH:36]=[CH:37][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)c2sc(NC(=O)c3ccccc3)nc12
Solvent: CC#N
Product: COc1ccc(N(Cc2ccc(C)cc2)C(=O)OCC(Cl)(Cl)Cl)c2sc(NC(=O)c3ccccc3)nc12
Temperature: 80 °C
Yield: 40.4 %

Procedure:
To a stirred solution of 300 mg (0.59 mmol) N-{7-[bis-(4-methyl-benzyl)-amino]-4-methoxy-benzothiazol-2-yl}-benzamide in 10 ml acetonitrile was added dropwise 0.60 ml (4.46 mmol) 2,2,2-trichloroethyl chloroformate and the reaction mixture heated at 80° C. for 72 h. The mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate/hexane) afforded 138 mg (40%) (2-benzoylamino-4-methoxy-benzothiazol-7-yl)-(4-methyl-benzyl)-carbamic acid 2,2,2-trichloro-ethyl ester as a yellow solid. ES-MS m/e (%):584 (M{37Cl, 37Cl, 37Cl}+H+, 5), 582 (M{37Cl, 37Cl, 35Cl}+H+, 32), 580 (M{37Cl, 35Cl, 35Cl}+H+, 100), 578 (M{35Cl, 35Cl, 35Cl}+H+, 92).
Reaction SMILES: [C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH:18]([NH2:21])([CH3:20])[CH3:19]>C(O)(C)C>[C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]([OH:15])[CH2:14][NH:21][CH:18]([CH3:20])[CH3:19])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(=O)NC=Cc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: CC(=O)NC=Cc1ccc(OCC(O)CNC(C)C)cc1

Procedure:
11.6 g (0.05 mol) of 1-[p-(2-acetylaminovinyl)-phenoxy]-2,3-epoxy-propane are dissolved in 100 ml of isopropanol, 4.25 ml (0.05 mol) of isopropylamine are added and thereafter the mixture is heated to the boil for 3 hours under reflux. It is then evaporated in vacuo and the resulting crude base is crystallised from ethyl acetate. 1-[p-(2-Acetylaminovinyl)-phenoxy]-2-hydroxy-3-isopropylaminopropane of melting point 144°-146° C. is obtained.