Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:12]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:6]2[N:7]=[C:8](Cl)[N:9]=[CH:10][C:5]=2[C:4](=[O:18])[C:3]=1[C:19]([NH2:21])=[O:20].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.O.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[NH2:1][C:2]1[N:12]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:6]2[N:7]=[C:8]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:27][CH:28]=3)[N:9]=[CH:10][C:5]=2[C:4](=[O:18])[C:3]=1[C:19]([NH2:21])=[O:20]
Reactant: NC(=O)c1c(N)n(C2CCCC2)c2nc(Cl)ncc2c1=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)c1c(N)n(C2CCCC2)c2nc(Nc3ccc(N4CCOCC4)cc3)ncc2c1=O
Temperature: 90 °C
Yield: 24.1 %

Procedure:
A mixture of 184 mg (0.60 mmol) of the product prepared in step 3.3 and 0.266 g (1.49 mmol) of N-(4-aminophenyl)morpholine (Lancaster) in 6 mL of NMP is placed in a 10 mL microwave tube. The sealed tube is placed in the microwave oven (CEM machine, Discover model) and the mixture is heated under pressure at 90°C. for 1 hour at a power of 100 W and then cooled to room temperature. 20 mL of water and then 5 mL of saturated aqueous NaHCO3 are added and the precipitate formed is drained by suction and dried in an oven. The crude solid is purified by chromatography on a column of silica, eluting with a dichloromethane/methanol gradient (98/2 to 95/5). 0.065 g of the expected product is obtained in the form of a beige-coloured powder. Yield=24%. m.p.=265°C. M+H+=450.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[C:17]([O:22][CH3:23])[CH:16]=2)[N:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[C:26]=1[F:33]>>[Cl:24][C:25]1[C:26]([F:33])=[C:27]([C:31]#[C:32][C:18]2[CH:19]=[CH:20][C:15]([N:11]3[C:12](=[O:14])[NH:13][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10]3)=[CH:16][C:17]=2[O:22][CH3:23])[CH:28]=[CH:29][CH:30]=1
Reactant: C#Cc1cccc(Cl)c1F
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1I
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C#Cc1cccc(Cl)c1F

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 3-(2-chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-32, 0.050 g, 0.11 mmol), 1-chloro-3-ethynyl-2-fluorobenzene
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ClCCl>CN(C)C=O>[CH2:20]([O:8][C:7]1[C:9]([O:10][CH3:11])=[CH:12][C:2]([CH:1]=[O:13])=[CH:3][C:4]=1[O:5][CH3:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C=O)cc(OC)c1OCc1ccccc1
Reaction time: 25 h
Yield: 87.6 %

Procedure:
To a stirring suspension of syringaldehyde (25.19 g, 138 mmol) and potassium carbonate (38.14 g, 276 mmol, 2 equ) in N,N-dimethyl formamide (500 ml) was added benzyl bromide (20 ml, 168 mmol, 1.2 equ). The reaction was stirred for 25 hours, then poured into dichloromethane. The organic solvent was washed with water (5×) then dried (MgSO4) and concentrated in vacuo to give a pink oil. This was recrystallised from hexane to give 31 (32.9 g, 87 %).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14])(=O)[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[OH:8][C:7]1[C:2]2=[N:1][C:9]([CH3:10])=[C:12]([CH2:17][CH2:16][OH:15])[C:13](=[O:14])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)C1CCOC1=O
Reactant: Nc1ncccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1nc2c(O)cccn2c(=O)c1CCO

Procedure:
During chemical development this process was altered. 2-Amino-3-hydroxypyridine was reacted with 2-acetyl-butyrolactone in the presence of p-toluenesulfonic acid in xylene to yield 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; this product proved to be poorly soluble in xylene resulting in deposit formation on the wall of the reaction vessel and discoloration of the reaction mixture to black.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]3[N:15]=[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=4)[C:13]([C:27]([O:29]CC)=[O:28])=[CH:12][N:11]=3)[CH2:6][C:5]=12.[OH-].[Na+].O1CCCC1>CS(C)=O.O>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]3[N:15]=[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=4)[C:13]([C:27]([OH:29])=[O:28])=[CH:12][N:11]=3)[CH2:6][C:5]=12
Reactant: CCOC(=O)c1cnc(N2CCn3ccnc3C2)nc1NCc1ccc(OC)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CCn4ccnc4C3)ncc2C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 97) 290 mg and 2N aqueous sodium hydroxide solution 1.64 ml are suspended in dimethyl sulfoxide-water (5 ml:1 ml) and stirred at room temperature for 1 hour. Tetrahydrofuran 5 ml is added thereto and the mixture is stirred at room temperature for 13 hours. After removal of tetrahydrofuran in vacuo, the residue is diluted with water and neutralized with a 10% aqueous citric acid solution. The precipitate is collected, washed with water, methanol and isopropyl ether to give 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-carboxypyrimidine as a colorless crystalline powder, 187 mg. mp 223-226° C. (decomposition), MS(m/z): 413(M−H)−
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[NH:19][CH:20]=[CH:21][C:14]=23)=[O:6])=[CH:26][CH:25]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 102.2 %

Procedure:
To a solution of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide (45 mg, 0.13 mmol), 4-methoxy benzaldehyde (16 uL, 0.13 mmol), and glacial acetic acid (8 uL, 0.13 mmol) in methanol (1 mL) was added sodium triacetoxy borohydride (84 mg, 0.4 mmol) portionwise. The solution was stirred at 50° C. for 18 h. The solution was absorbed onto Celite and purified by ISCO Companion (silica 0-10% methanol, methylene chloride, 1% ammonium hydroxide) to afford 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]-amide (56 mg, 75%) LCMS (ESI) 422 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 10.26 (1H, br. s.) 7.98-8.07 (2H, m) 7.77 (1H, d, J=5.47 Hz) 7.46 (1H, d, J=5.47 Hz) 7.30 (1H, d, J=3.32 Hz) 7.19 (2H, d, J=8.59 Hz) 6.76-6.84 (2H, m) 6.43 (1H, d, J=3.51 Hz) 3.69 (3H, s) 3.60 (2H, s) 3.33 (2H, q, J=6.25 Hz) 2.61 (2H, t, J=6.64 Hz)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([C:11]2([CH2:17][NH2:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[S:9][CH:10]=1.[F:19][C:20]([F:36])([F:35])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29](O)=[O:30])[N:22]=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([C:11]2([CH2:17][NH:18][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:23]4[N:22]=[C:21]([C:20]([F:36])([F:35])[F:19])[O:25][N:24]=4)[CH:27]=3)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[S:9][CH:10]=1
Reactant: NCC1(c2nc(-c3cccs3)cs2)CCOCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(c2nc(-c3cccs3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 46 %

Procedure:
This compound was synthesized from (4-(4-(thiophen-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (70 mg, yield 46%): 1H NMR (400 MHz, MeOD) δ 8.47 (t, J=1.5 Hz, 1H), 8.26 (m, 1H), 8.00 (dt, J=7.8 Hz, 1.4 Hz, 1H), 7.63-7.61 (m, 2H), 7.46 (dd, J=3.8 Hz, 1.0 Hz, 1H), 7.29 (dd, J=5.0 Hz, 1.0 Hz, 1H), 7.01 (dd, J=5.0 Hz, 3.8 Hz, 1H), 3.95-3.92 (dt, J=11.9 Hz, 4.0 Hz, 2H), 3.71 (s, 2H), 3.62-3.56 (m, 2H), 2.42-2.38 (d, J=13.8 Hz, 2H), 2.08-2.02 (ddd, J=14.3 Hz, 10.4 Hz, 4.4 Hz, 2H), MS (ESI) m/z: Calculated for C23H19F3N4O3S2: 520.09. found: 521.0 (M+H)+.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N+:27]([O-])=[CH:26][CH:25]=[CH:24]2)=[O:20])[CH3:17].[CH3:32][NH2:33].O1CCCC1>ClCCl>[CH3:32][NH:33][C:26]1[CH:25]=[CH:24][C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH:22]=2)[N:27]=1
Reactant: CCOC(=O)c1ccc2c(ccc[n+]2[O-])c1
Reactant: CN
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2nc(NC)ccc2c1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 35 %

Procedure:
Trifluoromethanesulfonic anhydride (1.92 mL, 11.4 mmol) was added dropwise to a −70° C. solution of 6-(ethoxycarbonyl)quinoline 1-oxide (2.25 g, 10.4 mmol) in dichloromethane (150 mL). The mixture was stirred at −70° C. for 5 minutes. Then a solution of methylamine in tetrahydrofuran (31 mL, 62 mmol, 2 M) was added dropwise. The mixture was stirred at −70° C. for 5 minutes. The reaction was quenched with water (20 mL). The layers were separated and the aqueous was extracted with dichloromethane (3×30 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave the title compound (850 mg, 35%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.33 (d, 1H), 8.16-8.13 (m, 1H), 7.90-7.87 (d, 1H), 7.70-7.67 (d, 1H), 6.68 (d, 1H), 5.30 (br. s., 1H), 4.43-4.38 (q, 2H), 3.13-3.12 (d, 3H), 1.44-1.40 (m, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Br[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:32]4[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Reactant: N#Cc1ccc(Br)cc1
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C#N)cc4)ccc3O2)CC1
Yield: 66 %

Procedure:
The title compound is prepared from 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester and 4-bromo-benzonitrile following a procedure analogous to that described in Example 1. Yield: 66% of theory; LC (method 1): tR=1.52 min; Mass spectrum (ESI+): m/z=391 [M+H]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>C1COCC1>[Br:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH:13]([CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[C:14]2=[O:19]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C1CCc2c(Br)cccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2Cc3c(Br)cccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.4 %

Procedure:
A solution of lithium diisopropylamide (2.0 M in THF, 2.5 mL, 5.0 mmol) was added to a solution of 4-bromo-2,3-dihydro-1H-inden-1-one (4-bromo-1-indanone, 960 mg, 4.55 mmol) in THF (9.1 mL) at −78° C. After 1 h at −78° C., a solution of methyl 4-(bromomethyl)benzoate (1.25 g, 5.46 mmol) in THF (5 mL) was added via cannula. The reaction mixture was allowed to warm to room temperature naturally. After stirring at room temperature overnight, the reaction was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (330 g column, hexanes→30% EtOAc/hexanes, gradient) to afford 72 mg (4%) of methyl 4-((4-bromo-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl)benzoate.
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH3:10])[CH2:3][CH2:4][CH2:5][C@H:6]([CH3:9])[CH:7]=[O:8].N1C(C)=CC=CC=1C.[Si:20](OS(C(F)(F)F)(=O)=O)([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22]>C(Cl)Cl>[CH3:9][C@@H:6]([CH2:5][CH2:4][CH2:3][C:2]([CH3:10])([O:1][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:11])[CH:7]=[O:8]
Reactant: C[C@H](C=O)CCCC(C)(C)O
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(C)(C)CCC[C@H](C)C=O
Temperature: 10 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a solution of aldehyde 9 (93.4 mg, 0.6 mmol) and 2,6-lutidine (170 μL, 1.5 mmol) in anhydrous CH2Cl2 (3.7 mL) was added dropwise Et3SiOTf (161 μL, 0.72 mmol) at 0° C. under argon. The solution was stirred at 10° C. for 3 hours and then at room temperature for 30 minutes. The mixture was quenched with cold water and extracted with CH2Cl2. The solvent was removed under reduced pressure, and the residue was chromatographed on silica Sep-Pak cartridge using hexane/EtOAc (99.7:0.3) as an eluent to give an oily aldehyde 10 (130 mg, 81%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].CO.Cl>C[O-].[Na+].O>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4]
Reactant: NCCCCC(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Yield: 79.4 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) and 5-amino-valeric acid (597 mg, 5.1 mmol) in 0.5 N NaOMe in MeOH solution (6.8 mL, 3.4 mmol) was heated to reflux overnight. Reaction mixture was diluted with water (100 mL) and acidified by 1 N HCl solution to pH=3-4. Precipitate was collected and rinsed with water. It was dried in vacuo to provide the title compound (102 mg, 0.27 mmol) in 80% yield. LC-MS ESI−: 379.07 (M−1)−.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:13][C:14](=[O:39])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:23]=[C:22]1[CH3:38])[CH3:12].I[CH2:41][CH3:42]>C1COCC1>[CH2:11]([O:13][C:14](=[O:39])[CH:15]([CH2:41][CH3:42])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:23]=[C:22]1[CH3:38])[CH3:12]
Reactant: CCI
Reactant: CCOC(=O)CCCCCCn1c(C)nc(-c2ccccc2)c1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)CCCCCn1c(C)nc(-c2ccccc2)c1-c1ccccc1

Procedure:
(Scheme 3 (O)) This compound was obtained using the procedures as described above. The following scales and reagents were used: 7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid ethyl ester (390 mg, 1 mmole), Sodium bis(trimethylsilyl)amide (1M in THF) (1.2 ml, 1.2 mmole), Iodoethane (0.4 ml, 779.8 mg, 5 mmole), anhydrous THF (10 ml). Product was obtained (100 mg, 24%). 1H NMR (CDCl3): δ0.88 (t, 3H), 1.23 (m, 4H), 1.33 (t, 3H), 1.54 (m, 4H), 1.68 (b, 1H), 2.04 (s, 1H), 2.17 (m, 1H), 2.49 (s, 3H), 3.709 (t, 2H), 4.15 (m, 2H), 7.19 (m, 3H), 7.42 (m, 3H), 7.46 (m, 4H). 13C NMR (CDCl3): δ12.0, 13.9, 14.6, 25.7, 26.6, 27.0, 30.5, 31.9, 44.0, 47.3, 60.2, 126.1, 126.7, 128.2, 128.7, 129.2, 131.3. Anal. Calcd. for C27H34N2O2: C, 77.48; H, 8.19; N, 6.69. Found: C, 77.34; N, 8.01; N, 6.56. Mass Spec: 419.32 (MH+).
Reaction SMILES: [C:1]([C:9](O)=[O:10])(=[O:8])C1C=CC=CC=1.[CH2:12]([OH:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:9]([O:30][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:10])[CH:1]=[O:8]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)C=O
Yield: 162.8 %

Procedure:
A solution of 5 g of benzoylformic acid (glyoxalic acid), 11.3 g of octadecanol and 0.19 g of p-toluenesulfonic acid in 60 ml of toluene is heated at reflux for 22 hours. The mixture is poured into saturated NaHCO3 solution and the phases are separated. The organic phases are washed with water and dried over sodium sulfate. Filtration and evaporation of the solvent give octadecyl glyoxalate (17.7 g) as a yellow solid. The product is recrystallized from methanol to give slightly yellowish crystals (11.29 g, 84%).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:22]([O-])([OH:24])=[O:23]>S(=O)(=O)(O)O>[C:1]([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[C:12]([N+:22]([O-:24])=[O:23])[CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc2ccccc2c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)Nc1ccc2cccc([N+](=O)[O-])c2c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 55.1 %

Procedure:
2-Ethoxalylamino-1-nitronaphthalene (11.5 g, 0.04 mol) was dissolved in 80 ml of sulfuric acid (d 1.84) by portionwise addition, with vigorous stirring on an ice-bath. Nitric acid (1.66 ml, 0.04 mol, d 1.52) in 20 ml of sulfuric acid (d 1.84) was added dropwise during 1 h at 0° C., and the mixture was stirred at this temperature for a further hour. The mixture was cautiously poured into 600 ml of ice/water with vigorous stirring. The yellow solid was collected, washed with water, and boiled with 300 ml of ethanol. The hot suspension was filtered and the undissolved residue was washed with 200 ml of ether to yield 7.35 g (55%) of the title compound,
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[CH2:4][N:5]=[C:6]=[S:7].[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)(C)C.C1C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[CH2:4][NH:5][C:6]([NH:16][CH2:15][CH2:13][OH:14])=[S:7]
Reactant: Cc1ccc(CN=C=S)c(C)c1
Reactant: NCCO
Solvent: c1ccccc1
Solvent: CC(C)O
Product: Cc1ccc(CNC(=S)NCCO)c(C)c1
Yield: 58 %

Procedure:
2,4-Dimethylbenzyl isothiocyanate (15.7 grams; 0.08 mole) was mixed with 23 milliliters (ml) of isopropyl alcohol and a solution of ethanolamine (5.8 grams; 0.08 mole) in 23 ml of isopropyl alcohol added dropwise thereto with stirring. The temperature of the reaction mixture was maintained below about 50°C during the ethanolamine addition and then stirred at ambient temperatures for a period of about 16 hours. The reaction mixture was then concentrated to dryness and the residue obtained taken up in benzene. The resulting benzene solution was cooled to give crystals which were filtered off. The title product was thus obtained in about a 58% yield as a crystalline solid having a melting point of 101-103°C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([CH:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:10](O)=[O:11])[CH3:8]>CCOCC>[CH2:7]([CH:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:10][OH:11])[CH3:8]
Reactant: CCC(CC(F)(F)F)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCC(CO)CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
A solution of LAH (2.74 g, 72.3 mmol) in Et2O (230 mL) was stirred under nitrogen at 0° C. 2-Ethyl-4,4,4-trifluorobutyric acid (12.3 g, 72.3 mmol) in Et2O (20 mL) was added dropwise, and the solution stirred for 15 min at 0° C. and then 2 h at 25° C. After this time period, the solution was quenched with the dropwise addition of H2O (2.74 mL), 15% NaOH (2.74 mL), and H2O (8.22 mL) with efficient stirring. Solid Na2SO4 was added to dry the solvent, and the resulting mixture was stirred for 1 h. The resulting slurry was filtered, and the filter cake washed with excess Et2O. After concentration, the crude product was purified by the Biotage Flash™ 40 chromatography instrument, eluent: 20:80 to 30:70 Et2O:PE to obtain 2-ethyl-4,4,4-trifluorobutanol as an oil (6.18 g, 55% yield for two steps).
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[C:4]([I:16])[N:3]=1.C([Li])CCC.O.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[I:16][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:7]([O:8][CH3:9])=[CH:2][N:3]=1
Reactant: COCCCCc1cc(I)nc(I)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCCCCc1cc(I)ncc1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2 mmol of 2,6-diiodo-3-methoxy-4-(4-methoxy-butyl)-pyridine are added to a solution of 4 mmol n-butyllithium in 1.6 ml hexane and 10 ml tetrahydrofuran at −78° C. under an argon atmosphere. The reaction mixture is stirred at −78° C. for 15 minutes. 2 mmol of water are introduced and the reaction mixture is warmed to room temperature. 10% Aqueous ammonium chloride solution is added to the mixture followed by extraction with tert-butyl methyl ether (3×). The combined organic layers are dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60 F) and identified based on its Rf value.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6](=[O:18])[CH2:7][N+:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.C(=O)(O)[O-].[Na+].[C:36](#[N:39])[CH:37]=[CH2:38]>CN(C)C=O>[Br:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([C:7]1[N:8]2[C:17]3[C:12]([CH:11]=[CH:10][C:9]2=[C:37]([C:36]#[N:39])[CH:38]=1)=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:18]
Reactant: C=CC#N
Reactant: O=C(C[n+]1cccc2ccccc21)c1cccc(Br)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)c2cccc(Br)c2)n2c1ccc1ccccc12

Procedure:
The title compound was prepared from 1-(3-bromo-phenacyl)-quinolinium bromide (150 mg, 0.368 mmol), tetrapyridinecobalt(II) dichromate (306 mg, 0.502 mmol), sodium bicarbonate (96.3 mg, 1.15 mmol), acrylonitrile (150 μL, 2.28 mmol), and N,N-dimethylformamide (4.0 mL), similar to Example 1b, and yielded 21.2 mg (15%) as a yellow solid. 1H NMR (CDCl3): 8.20 (t, J=1.79 Hz, 1H), 8.06 (d, J=8.51 Hz, 1H), 7.98 (dt, J=6.25, 1.38 Hz, 1H), 7.86 (dd, J=7.83, 1.51 Hz, 1H), 7.81 (ddd, J=6.52, 2.06, 0.96 Hz, 1H), 7.76 (d, J=9.06 Hz, 1H), 7.69 (d, J=9.06 Hz, 1H), 7.63 (ddd, J=8.31, 7.14, 1.65 Hz, 1H), 7.56 (td, J=7.41, 1.10 Hz, 1H), 7.45 (t, J=7.83 Hz, 1H), 7.44 (s, 1H).