Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[C:10]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)=[C:9]2[C:38]#[N:39])=CC=1.[N-:42]=[N+:43]=[N-:44].[Na+].[NH4+].[Cl-]>C[N-]C.ClCCl.FC(F)(F)C(O)=O>[CH3:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[NH:8][C:9]([C:38]1[NH:39][N:44]=[N:43][N:42]=1)=[C:10]2[CH2:24][CH2:25][CH2:26][O:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(Cn2c(C#N)c(CCCOc3cccc4ccccc34)c3cccc(-c4ccccc4C)c32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: C[N-]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1-c1cccc2c(CCCOc3cccc4ccccc34)c(-c3nnn[nH]3)[nH]c12
Temperature: 125 °C

Procedure:
To a mixture of EXAMPLE 581D (232 mg) in N, N-dimethylamide (10 ml) was added NaN3 (281 mg) and NH4Cl (231 mg). The mixture was stirred at reflux overnight. The mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate (200 ml) and water (60 ml). The organic phase was washed with brine and dried over Na2SO4. Concentration of the solvent gave crude product which was dissolved in dichloromethane/trifluoroacetic acid (1:1, 4 ml) and heated to 125° C. in a microwave (CEM Discover) for 20 minutes. The mixture was concentrated and the residue was dissolved in dimethylsulfoxide/methanol (1/1, 2 ml) and loaded on HPLC for purification. 1H NMR (300 MHz, DMSO-d6) δ 10.63 (m, 1H), 8.26 (m, 1H), 7.86 (m, 1H), 7.74 (d, 1H), 7.53 (m, 2H), 7.42 (m, 5H), 7.33 (m, 2H), 7.11 (m, 3H), 6.90 (d, 1H), 4.23 (t, 2H), 2.29 (m, 2H), 2.13 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>CN(C=O)C>[Cl:10][C:4]1[CH:3]=[C:2]([N:1]([CH2:6][C:5]2[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-2-chlorobenzonitrile (1.0 g, 6.56 mmol, 1 eq) and benzyl bromide (3.12 mL, 26.2 mmol, 4.0 eq) in dry DMF (10 mL) was added at rt NaH (1.31 g, 32.8 mmol, 5 eq) portionwise under Ar(g). The reaction mixture was stirred at rt overnight, and was subsequently partitioned with H2O (30 mL) and extracted with EtOAc (5×20 mL) and CH2Cl2 (20 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (1:0-9:1) to yield the product, 2, as a white solid (1.72 g, 79%);
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].Cl.[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH:18]3[N:19]4[CH2:29][CH2:28][N:27]=[C:20]4[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[N:17]3[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C(Cl)Cl.N1C=CC=CC=1>[ClH:5].[CH3:1][S:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH:18]3[N:19]4[CH2:29][CH2:28][N:27]=[C:20]4[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[N:17]3[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: Oc1ccc(C2CCN3c4ccccc4C4=NCCN4C23)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc(C2CCN3c4ccccc4C4=NCCN4C23)cc1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
6 ml of methylsulfonyl chloride were added dropwise at 0°-5° C. to a vigorously stirred suspension of 8.55 g of 2,3,5,6,7,8-hexahydro-5-(4-hydroxyphenyl)imidazo[1,2-c]pyrrolo[1,2-a]quinazoline hydrochloride in 100 ml of methylene chloride and 25 ml of pyridine, and the reaction mixture was stirred at room temperature for 70 h. The solvent was removed by distillation and then 1N HCl was added, and the resulting precipitate was recrystallized from ethanol/methyl t-butyl ether. Yield: 8.0 g (76%); melting point 241°-242° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([OH:27])=O)=[N:10]2)=[CH:5][CH:4]=1.[O:28]1[C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1>CN(C)C=O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[CH:14]([O:23][CH2:24][C:25]([N:35]4[CH2:36][CH:37]5[O:28][CH2:29][CH2:30][O:31][CH:32]5[CH2:33][CH2:34]4)=[O:27])[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:21]3=[O:22])=[N:10]2)=[CH:5][CH:4]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)N3CCC4OCCOC4C3)nc2n1
Yield: 81.7 %

Procedure:
The procedure is as in Example 44, but starting with [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid (3 g) in anhydrous dimethylformamide (65 cc), N,N'-carbonyldiimidazole (1.35 g) and 1,4-dioxa-8-azaspiro[4.5]decane (1 g). After two successive recrystallizations in carbon tetrachloride and isopropyl ether, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-[2-(4-ethylenedioxypiperidino)-2-oxoethoxy]-1-isoindolinone (2.8 g), m.p. 137° C., is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:18])[C:6]=2[CH:19]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[CH:3]=[CH:4][C:5]3[N:10]=[N:9][N:8]([CH2:11][C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[C:7](=[O:18])[C:6]=3[CH:19]=2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=c1c2cc(Br)ccc2nnn1Cc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=c1c2cc(Oc3ccc(Cl)cc3)ccc2nnn1Cc1cccnc1
Yield: 49.4 %

Procedure:
A mixture of 10.0 g of 6-bromo-3-(3-pyridylmethyl)-1,2,3-benzotriazin-4 (3H)-one, 6.1 g of 4-chlorophenol, 9.4 g of cupric oxide, 13.1 g of potassium carbonate and 100 ml of pyridine was refluxed under heating for 9 hours. After finishing the reaction, the insoluble material was filtered off, and the filtrate was concentrated in vacuo. The resulting residue was chromatographed on a column of silica gel, developing with ethyl acetate/hexane=1:1 and then recrystallized from hexane-methylene chloride to give 5.68 g of the titled compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:48])[CH2:14][CH2:13][CH:12]([C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23](C2CCCCO2)[N:22]=[C:21]3[C:33]2[NH:37][C:36]3[CH:38]=[CH:39][C:40]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:41][C:35]=3[N:34]=2)=[O:16])[CH2:11][CH2:10]1>C(Cl)Cl>[F:48][C:9]1([F:8])[CH2:10][CH2:11][CH:12]([C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[C:33]2[NH:37][C:36]3[CH:38]=[CH:39][C:40]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:41][C:35]=3[N:34]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CCC(F)(F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3nc4cc(N5CCOCC5)ccc4[nH]3)c2c1)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
TFA (0.082 mL, 1.063 mmol) was added to a solution of 4,4-difluoro-N-(3-(5-morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclohexanecarboxamide (6 mg, 10.63 μmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature, and the solvent was removed in vacuo. Purification by flash column chromatography (5% CH3OH/CH2Cl2) afforded the title compound (4 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.46 (s, 1H), 7.69 (m, 1H), 7.57 (m 2H), 7.18 (d, 1H, J=1.6 Hz), 7.07 (dd, 1H, J=2.0 and 8.8 Hz), 3.88 (m, 4H), 3.18 (m, 4H), 2.55 (m, 1H), 2.17 (m, 2H), 2.01 (m, 2H), 1.96-1.83 (m, 4H); ESI-MS [M+H]+: 481.28.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.[OH:25][CH:26]([C:30]#[CH:31])[C:27](O)=[O:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[OH:25][CH:26]([C:30]#[CH:31])[C:27]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:28]
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Reactant: C#CC(O)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC(O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (75 mg, 0.23 mmol) in 0.78 ml CH2Cl2 were added successively 2-hydroxybut-3-ynoic acid (30 mg, 0.30 mmol), BOP (134 mg, 0.30 mmol), and triethylamine (36 mg, 49 μL, 0.35 mmol). The mixture was stirred at 0° C. for 30 minutes. Purification via silica gel chromatography using 0-100% ethyl acetate/hexanes gave 2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)but-3-yn-1-one. (LC/MS: m/z 403.5 (M+H)+ at 2.34 min (10% O-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C1([SiH3])C=CC=CC=1.[N+:58](/[CH:61]=[C:62](/[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)\[CH3:63])([O-:60])=[O:59].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CC(C)([O-])C.[Cu+].C1(C)C=CC=CC=1.O.O1CCCC1>[N+:58]([CH2:61][CH:62]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[CH3:63])([O-:60])=[O:59]
Reactant: C/C(=C\[N+](=O)[O-])c1ccccc1
Agent: [Cu+]
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
In a 10 mL Schlenk-flask, 6.8 mg of copper (I) tert-butoxide and 32.7 mg (55 μmol) of (S)-p-tol-BINAP were dissolved in 5 ml of toluene. After stirring for 30 minutes at room temperature to give an asymmetric copper complex. This solution to the amount containing 1 μmol of the asymmetric copper complex were mixed with 4.9 ml of toluene, and 6 μL (0.1 mmol) of poly(methylhydrosiloxane) (15-40 mPas (20° C.), d=1.004 g/mL, nD20=1.398, produced by Fluka) were added thereto. Further, 185 μL of (1.5 mmol) of phenylsilane and 27 μL (1.5 mmol) of water were added. After stirring for 5 minutes, 1 mmol of (E)-1-nitro-2-phenyl-1-propene was added, and the mixture was further stirred for 24 hours at room temperature. Four milliliters (4 mL) of a tetrahydrofuran solution of tetrabutylammonium fluoride (1 mol/L) were added to the reaction mixture and stirring was continued for 3 hours. Water was added and the mixture was extracted with diethyl ether (30 mL×2). After drying over sodium sulfate, the solvent was evaporated. The residue was purified by flash chromatography (silica gel, hexane/ethyl acetate) to provide optically active 1-nitro-2-phenylpropane.
Reaction SMILES: O=[C:2]([CH:8]1[C:17](=O)[C:16]2[C:11](=[CH:12][C:13]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:14][CH:15]=2)[S:10][CH2:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OC([NH:31][NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]1)=O)(C)(C)C.Cl>CCO>[NH:35]1[CH2:36][CH2:37][CH2:38][CH:33]([N:32]2[C:17]3[C:16]4[CH:15]=[CH:14][C:13]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=4[S:10][CH2:9][C:8]=3[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:31]2)[CH2:34]1
Reactant: CCOC(=O)C(=O)C1CSc2cc(OC(F)(F)F)ccc2C1=O
Reactant: CC(C)(C)OC(=O)NNC1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1nn(C2CCCNC2)c2c1CSc1cc(OC(F)(F)F)ccc1-2
Temperature: 75 °C
Yield: 84.2 %

Procedure:
To a solution of ethyl oxo[4-oxo-7-(trifluoromethoxy)-3,4-dihydro-2H-thiochromen-3-yl]acetate (3.00 g; 8.61 mmol; 1 eq.) and tert-butyl 3-[2-(tert-butoxycarbonyl)hydrazino]piperidine-1-caroxylate (4.08 g; 12.92 mmol; 1.50 eq.) in EtOH (80 ml) is added HCl (4M in dioxane, 42.38 mL) were added in a dropwise fashion. Reaction mixture is heated at 75° C. for 5 h after which it is concentrated under vacuum, partitioned between NaHCO3 sat (pH 7-8) and EtOAc. Organic layer is washed NaHCO3 sat and brine, dried over MgSO4 to give 3.1 g (88%) of the title compound as a brown solid. 1H NMR (DMSO, 300 MHz): δ 7.77 (d, J=9.43 Hz, 1H), 7.62 (s, 1H), 7.39 (d, J=7.7 Hz, 1H), 4.61-4.46 (m, 1H), 4.40-4.26 (m, 2H), 4.17 (s, 1H), 4.09-3.98 (m, 1H), 3.19-3.06 (m, 1H), 2.97-2.82 (m, 2H), 2.17-2.05 (m, 2H), 1.99 (s, 1H), 1.80-1.67 (m, 1H), 1.67-1.45 (m, 1H), 1.32 (t, J=7.0 Hz, 3H), 1.18 (t, J=6.9 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15](OCC)=[O:16])=[N:12][CH:11]=2)=[CH:6][CH:5]=1.O.[NH2:23][NH2:24]>CCO>[F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([NH:23][NH2:24])=[O:16])=[N:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: NN
Reactant: CCOC(=O)c1ncc(-c2ccc(OC(F)(F)F)cc2)o1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ncc(-c2ccc(OC(F)(F)F)cc2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of ethyl 5-(4-(trifluoromethoxy)phenyl)oxazole-2-carboxylate (6.4 g, 21.2 mmol) in EtOH (30 mL), was added dropwise hydrazine hydrate (6 mL, 84% in H2O) while stifling at RT. The mixture was then stirred for further 16 h at RT and then concentrated under reduced pressure to half volume. Upon addition of H2O (30 mL) a yellow solid precipitated, which was filtered, washed with H2O (3×30 mL) and dried to afford the title compound as a light yellow solid (4.6 g, 75%). MS (ES+) C11H8F3N3O3 requires: 287. found: 288 [M+H]+;
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([CH3:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CN(C)[CH:34]=[O:35]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:34]=[O:35])=[N:3][CH:4]=[C:5]([CH3:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(C)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1C=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
To a solution of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (750 mg, 1.59 mmol) in THF (3 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF). The mixture was then stirred for 30 min at 0° C. followed by the addition of N,N-dimethylformamide (1.19 mL, excess) at 0° C. The mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2×25 mL). Combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. Obtained residue was column purified (SiO2, 30% EtOAc-hexanes) to obtain 4-chloro-N-(2-formyl-5-methyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (300 mg) in 44.7% yield. ESMS m/z (relative intensity): 390.9 (M−32+H)+ (40), 423 (M+H)+ (40), 444.9 (M+Na)+ (40).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
An 18-mL vial was charged with give methyl 4-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]butanoate (10 mg, 0.024 mmol, 1 eq.) and lithium hydroxide monohydrate (45 mg, 1.07 mmol, 44 eq.). To this was added THP (1 ml) and water (0.5 ml). The resulting mixture was stirred at room temperature overnight. Then 1N HCl aq. (1 ml) was added. The volatile materials were removed under reduced pressure to give a residue, which was purified by chromatography on silica gel using 2˜4% of MeOH in dichloromethane as eluent to give the title compound (7.8 mg, 80% yield). MW=406.90. 1H NMR (DMSO-D6, 400 MHz) δ 8.11 (s, 1H), 7.91 (s, 1H), 7.74 (m, 1H), 7.42 (m, 2H), 7.20 (m, 5H), 2.93 (m, 2H), 2.82 (m, 2H), 2.58 (m, 2H), 2.26 (m, 2H), 2.10 (m, 2H), 1.79 (m, 2H).
Reaction SMILES: [C:1]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:49]1[C:54](=[O:55])[CH2:53][CH2:52][C:50]1=[O:51])=[N+](C)C)C>C1COCC1>[C:18]([O:20][N:49]1[C:54](=[O:55])[CH2:53][CH2:52][C:50]1=[O:51])(=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)[O-]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 18 h
Yield: 29 %

Procedure:
To a solution of mono-tert-butyl octadecanedioate (1.00 g, 2.7 mmol) in dry THF (8 ml), was added DIPEA (0,555 ml, 3.2 mmol) followed by TSTU (1.00 g, 3.2 mmol). The reaction mixture was stirred under nitrogen for 18 h. The solvent had evaporated. AcOEt was added to the residue and the resulting suspension was filtered. The filtrate was washed with cold 0.1 M HCl (2×) and water, dried and concentrated to give succinimidyl tert-butyl octadecandioate as a white solid.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH:12](=O)/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH:13](/[CH:12]1[O:1][CH:2]([CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:10][O:11]1)=[CH:14]\[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCC/C=C/C=C/C=O
Reactant: COC(=O)CCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: CCCCCCCCCC/C=C/C=C/C1OCC(CCCC(=O)OC)O1

Procedure:
Methyl 5,6-dihydroxyhexanoate (0.32 g, 2.0 mmol),2E,4E -pentadecadienal (0.445 g, 2.0 mmol) and catalytic pyridinium p-toluene sulfonate (PPTS) were refluxed in 10 ml of benzene with a Dean Stark trap for 21 hours. The mixture was cooled, filtered, and concentrated. Flash chromatography with 25:1+20:1 hexane/ethyl acetate provided methyl 2-tetradeca-1E,-3E-dienyl-1, 3-dioxolane-4-butanoate as 21 mg of isomer B as a crystalline solid, 25 mg of isomer A, as a crystalline solid, and 68 mg of a mixture of A and B.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][CH3:11])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([CH2:9][CH2:10][CH3:11])[CH:3]=1
Reactant: CCCc1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(Br)ccc1OCc1ccccc1
Yield: 90.9 %

Procedure:
To a 100 ml acetone solution of 4-bromo-2-propylphenol 5.4 g (25.1 mmol) and benzyl bromide 5.6 g (32.7 mmol) was added potassium carbonate 5.2 g (37.6 mmo). Resulting suspension was stirred under reflux temperature for overnight. Acetone was removed under reduced pressure, diluted with ethyl acetate and water. Organic phase was separated. Aqueous phase was extracted with ethyl acetate twice. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, chromatographed on silica gel (hexanes:t-butyl methyl ether) to give 6.96 g of benzyl 4-bromo-2-propylphenyl ether as colorless oil.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[CH-:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.[Fe+2:25].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:1]([CH2:9][CH2:10][CH2:11][C:12]([C-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH-:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.[Fe+2:25]
Reactant: O=C(Cl)CCCC(=O)c1ccccc1
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCCC(=O)[c-]1cccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3 %

Procedure:
4-Benzoylbutryl chloride (assumed to be 0.005 mole) and ferrocene (0.97g; 0.005 mole) in dry methylene chloride (25 ml) were stirred at 0°-5° and aluminium chloride (1.04g; 0.011 mole) was added. The mixture was stirred at room temperature for 30 minutes, ice was added slowly and the organic fraction was separated. The aqueous fraction was extracted with chloroform and the combined organic fractions were washed with water, dried (magnesium sulphate) and evaporated. The resulting oil was purified by column chromatography on silica using 9:1 petroleum ether: ethyl acetate as eluent to yield a yellow solid which was recrystallised from petroleum ether to yield pure 4-benzoylbutyrylferrocene mp 96° (3%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[C:33]2[CH3:37])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[C:33]4[CH3:37])[CH:27]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: Cc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccccc3F)ccc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nccn1-c1cccc(C2=Nc3ccc(-c4ccccc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from (2′-fluoro-3-{3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K52) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (174 mg).
Reaction SMILES: Cl.O.C([O:5][C:6](=[O:21])[CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[I:20])C(OCC)=O)C>CCOCC>[I:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][CH2:7][C:6]([OH:21])=[O:5]
Reactant: CCOC(=O)C(Cc1ccccc1I)C(=O)OCC
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: O=C(O)CCc1ccccc1I

Procedure:
Concentrated HCl (2.3 mL) and water (0.3 mL) was added to 2-(2-iodo-benzyl)-malonic acid diethyl ester (1.4 g, 3.6 mmol) and the mixture was refluxed overnight. Starting material could still be seen on TLC. More concentrated HCl (2 mL) was added and the mixture was refluxed overnight. Water (20 mL) and ether (50 mL) was added to the mixture. The two phases was separated. The organic phase was extracted with an ammonium hydroxide solution (5N, 30 mL). The basic water phase was added slowly to ice-cold conc. HCl. The white precipitate was filtered and washed with ice-cold water and the solvent was removed in vacuo. Yield: 0.32 g, 32%.