Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:21][CH3:22])=[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[CH2:5][NH:4]1)[CH3:2].CCN(C(C)C)C(C)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br.[Cl-].[NH4+]>CN(C=O)C.O>[CH2:1]([CH:3]1[CH2:12][CH:11]2[C:6](=[CH:7][C:8]([O:21][CH3:22])=[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[CH2:5][N:4]1[CH2:37][C:36]1[CH:39]=[CH:40][CH:41]=[C:34]([O:33][CH3:32])[CH:35]=1)[CH3:2]
Reactant: COc1cccc(CBr)c1
Reactant: CCC1Cc2cc(OCc3ccccc3)c(OC)cc2CN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCC1CC2CC(OCc3ccccc3)=C(OC)C=C2CN1Cc1cccc(OC)c1
Temperature: 25 °C

Procedure:
A solution of 261 (297 mg, 1.0 mmol) in anhydrous DMF (3.0 mL), DIPEA (263 mg, 2.0 mmol) and 3-methoxybenzyl bromide (222 mg, 1.1 mmol) was heated to 80° C. for 12 h, cooled to room temperature and poured into water (50 mL) and ammonium chloride (saturated, 2 mL). The mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography using Flashmaster (SiO2: 20 g, hexane 100% to hexane/ethyl acetate 70:30). The title compound was obtained as pale yellow oil (323 mg, 77%). 1H NMR (270 MHz, CDCl3) δ 1.02 (3H, t, J 7.4, CH2CH3), 1.46 (1H, sept, J 7.2, one of CH2CH3), 1.73 (1H, sept, J 6.8, one of CH2CH3), 2.55 (1H, dd, J 16.2, 6.1, one of ArCH2CH), 2.82 (1H, dd, J 16.2, 5.0, one of ArCH2CH), 2.85-2.98 (1H, m, CHN), 3.61-3.77 (4H, m, 2×ArCH2N), 3.84 (6H, s, 2×OCH3), 5.16 (2H, s, OCH2Ph), 6.52 (1H, s, CH), 6.67 (1H, s, CH), 6.81-6.87 (1H, m, CH), 6.95-7.02 (2H, m, 2×CH), 7.23-7.52 (5H, m, OCH2C6H5), 7.27 (1H, t, J 6.9, CH).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[CH3:41][C@@H:39]1[CH2:40][N:35]([C:21]2[C:20]([CH2:19][OH:18])=[CH:33][C:24]3[C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:26][O:27][C:23]=3[C:22]=2[F:34])[CH2:36][C@H:37]([CH3:42])[O:38]1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204, 693 mg, 1.17 mmol) was dissolved in THF (3 ml) along with acetic acid (0.134 ml, 2.35 mmol). TBAF (1N in THF, 1.290 ml, 1.29 mmol) was added and the reaction was stirred at room temperature for 30 minutes. The reaction was diluted with water and extracted 2× with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N+:18]([O-])=O)[CH:12]=3)[N:10]=2)[N:7]=1.CC(O)=O>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([CH:12]=3)[NH2:18])[N:10]=2)[N:7]=1
Reactant: Cc1ccc(-c2nc3ccc(Cl)nn3c2C)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc3ccc(Cl)nn3c2C)cc1N
Temperature: 80 °C
Yield: 80.6 %

Procedure:
To a mixture of 6-chloro-3-methyl-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (2.00 g, 6.60 mmol) in ethanol (100 mL) and water (25 mL) containing AcOH (39.6 mmol) is added iron (1.84 g, 33.0 mmol). The mixture is heated at 80° C. for 6 hours, then cooled, concentrated under reduced pressure and sat. aqueous NaHCO3 (100 mL) is added. The mixture is extracted with EtOAc (3×50 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude is purified via chromatography (hexanes to EtOAc) to afford the title compound (1.45 g, 80%) as a yellow solid: Rf 0.52 (EtOAc); LCMS (m/z)=273.3, 275.3 [M+H]+, tR=1.79 min.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[CH:5][CH:4]=1.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: FC(F)(F)c1ccc(CC2c3ccccc3CCc3ccccc32)cc1
Reaction time: 17 h

Procedure:
Add the 5-(4-trifluoromethyl-benzylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.14 g, 0.45 mmol), to a mixture of 10% Pd/C (0.05 g) suspended in absolute ethanol (4.0 mL) and ethyl acetate (4.0 mL) and hydrogenate under a balloon of hydrogen at room temperature and pressure. Stir for 17 h, remove the catalyst via filtration through a pad of Celite. Evaporate the filtrate and pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to gives the title product. MS (m/e): 352 (M+); Analysis for C23H19F3: Calcd: C, 78.39 H, 5.43. Found: C, 78.70 H, 5.16.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]=[C:25]=[O:26].O.N.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:25]([NH:24][CH3:23])=[O:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN=C=O
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccccc2N)CC1
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)Nc1ccccc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
After dissolving 400 mg of 1-(tert-butoxycarbonyl)-4-(2-aminophenoxymethyl)piperidine in 10 ml of tetrahydrofuran, 458 mg of methyl isocyanate was added and the mixture was stirred overnight at room temperature. Ammonia water was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then filtered with NH silica gel. The solvent was distilled off under reduced pressure to obtain the title compound (469 mg, 99% yield).
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cu][C:11]#[N:12]>CN(C=O)C.CCOC(C)=O.O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:11]#[N:12])=[C:3]([CH3:9])[CH:4]=1
Reactant: N#C[Cu]
Reactant: Cc1cc(N)ncc1Br
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(N)ncc1C#N
Temperature: 200 °C
Yield: 32 %

Procedure:
A mixture of 5-bromo-4-methyl-2-pyridinamine (0.50 g, 2.7 mmol) and copper (I) cyanide (0.263 g, 2.9 mmol) in DMF (12 mL) was heated at 200° C. for a total of 1.75 h in a microwave reactor. The reaction mixture was diluted with EtOAc and water. The resulting thick dark precipitate was filtered off. The filtrate was extracted with EtOAc (×3) and the combined extracts were dried and concentrated to give a dark yellow solid (0.115 g). The filter cake was and washed with 1:1 DCM/MeOH (1 L) which was concentrated to give a second batch of dark yellow solid (0.047 g). The filter cake was washed with 2M NH3 in MeOH (200 mL) which was concentrated to give a dark green solid (0.533 g). These 3 batches of solids were purified by column chromatography using 0-100% EtOAc/hexane as the eluent to give the title compound as a white solid (total yield: 0.213 g). δH (CDCl3, 400 MHz) 8.28 (1H, s), 6.36 (1H, s), 4.87 (2H, br.s), 2.40 (3H, s). MS (ES): MH+ 134.1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>O1CCCC1>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[C:18](=[O:20])[CH3:19]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of N-methyl-4-nitroaniline (5.00 g, 32.9 mmol) and pyridine (7.97 ml, 98.6 mmol) in tetrahydrofuran (100 ml) was added acetyl chloride (3.51 ml, 49.4 mmol) with ice-cooling, the mixture was stirred for 3 hours with ice-cooling, the reaction mixture was poured into ice-water and the desired product (2.60 g, 40.7%) as a solid was collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:21])[C@H:16]([CH:18]([CH3:20])[CH3:19])[NH2:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:31]([C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](O)=[O:37])#[N:32].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH:14][C:15](=[O:21])[C@H:16]([CH:18]([CH3:20])[CH3:19])[NH:17][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][CH:41]=[C:33]([C:31]#[N:32])[CH:34]=3)[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: CC(C)[C@H](N)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cccc(C#N)c1)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-{(valylamino)methyl}piperidine (20 mg, 0.059 mmol) in CH2Cl2 (0.60 mL) was treated with Et3N (0.011 mL, 0.077 mmol), m-cyanobenzoic acid (28 mg, 0.071 mmol), EDCI (13 mg, 0.065 mmol) and HOBt (9 mg, 0.065 mmol). The reaction mixture was stirred at 25° C. for 16 h. The resulting solution was diluted with CH2Cl2 (0.75 mL), washed with 2 N aqueous NaOH solution (2×0.75 mL) and dried by filtration through a PTFE membrane. Concentration afforded the 1-(4-chlorobenzyl)-4-[{N-(3-cyanobenzoyl)valyl}aminomethyl]piperidine (compound No. 619) (24.2 mg, 88%) which required no further purification: The purity was determined by RPLC/MS (85%); ESI/MS m/e 467 (M++H, C26H31ClN4O2).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[C:6]([O:13][CH3:14])[CH:5]=1)([OH:3])=O.[CH:15]([NH2:18])([CH3:17])[CH3:16]>>[CH:15]([NH:18][C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[O:3])([CH3:17])[CH3:16]
Reactant: COc1cc(C(=O)O)ccc1B(O)O
Reactant: CC(C)N
Product: COc1cc(C(=O)NC(C)C)ccc1B(O)O

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate K from 4-carboxy-2-methoxyphenyl boronic acid and isopropylamine. The solvent was removed and then water and EtOAc were added. The phases were separated and the aqueous one was extracted twice with EtOAc. The organic extracts were combined and dried (Na2SO4), and concentrated. The residue was triturated in acetonitrile to give the title compound. tR: 0.63 min (LC-MS 2); ESI-MS: 238.5 [M+H]+ (LC-MS 2).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:6]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:26]1C=CC(C(C)(C)C)=C(OC2C=CC(CC)=CC=2)C=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si:13]([CH3:15])([CH3:14])[CH3:16])=[CH:7][C:6]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH3:26])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(Oc2cc(Br)ccc2C(C)(C)C)cc1
Reactant: Cc1ccc(Oc2cc(C#C[Si](C)(C)C)ccc2C(C)(C)C)cc1
Product: CCc1ccc(Oc2cc(C#C[Si](C)(C)C)ccc2C(C)(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of 2-tert-butyl-5-trimethylsilanylethynyl-1-[(4′-methyl)phenoxy]benzene (Compound U), 52 mg (0.16 mmol) 5-bromo-2-tert-butyl-1-[(4′-ethyl)phenoxy]benzene (Compound T) was converted into the title compound using 28 mg (0.04 mmol) of bis(triphenylphosphine)palladium (II) chloride, 7 mg (0.04 mmol) of cuprous iodide, 0.2 mL (150 mg, 1.5 mmol) of trimethylsilyl acetylene and 3 mL of triethylamine. An additional 28 mg (0.04 mmol) of bis(triphenylphosphine)palladium (II) chloride, and 0.2 mL (150 mg, 1.5 mmol) of trimethylsilyl acetylene were added after 3 days of heating, and the resultant mixture was then heated at 75° C. for 4 more days. Purification by flash chromatography (preabsorbed onto silica with 100% chloroform, eluted with 100% hexane) gave the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH2:10][C:11]([C:33]([OH:35])=O)=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:36]([O:43][CH2:44][CH2:45][CH2:46][NH:47][CH2:48][CH2:49][CH3:50])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[Si:36]([O:43][CH2:44][CH2:45][CH2:46][N:47]([CH2:48][CH2:49][CH3:50])[C:33]([C:11]1=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10]1)=[O:35])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]
Reactant: CCCNCCCO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)O)C1
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by the procedure as described in Example 101 (Step H) using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and 3-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine. MS APCI(+) m/z 689 detected.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1[C:22]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:21][CH:20]=[CH:19][N:18]=1.Br[C:28]1[C:33](OCC)=CC=CN=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:28][CH3:33])[C:15]2[C:22]([O:23][CH:24]([CH3:25])[CH3:26])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cccnc1Br
Reactant: CC(C)Oc1cccnc1Br
Reactant: CNC1CCN(Cc2ccccc2)CC1
Product: CCN(c1ncccc1OC(C)C)C1CCN(Cc2ccccc2)CC1

Procedure:
Following the general procedure of EXAMPLE 70, and making non-critical variations but substituting 1-benzyl-4-(ethylamino)piperidine (EXAMPLE 11) for 1-benzyl-4-(methylamino)piperidine and 2-bromo-3-(1-methylethoxy)pyridine (EXAMPLE 76) for 2-bromo-3-ethoxypyridine, the title compound is obtained, NMR (CDCl3) 7.84, 7.32-7.22, 6.99, 6.68, 4.52, 3.82, 3.49, 3.40, 2.94, 2.00, 1.85, 1.73, 1.31 and 1.02δ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1>C(O)C>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH2:10])[CH2:5][CH2:4]1
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Product: COC1CCC(CN)CC1
Reaction time: 26 h

Procedure:
(4-Methoxyphenyl)methanamine (1 g) in ethanol (10 ml) was treated with 5% dry Rh—Al2O3 (0.5 g) under H2 (500 psi) at 60° C. for 6 hours and then at 125° C. for 26 hours. The insoluble material was filtered off and the filtrate was concentrated to provide the title compound.
Reaction SMILES: O1CCCC1.[CH:6](=[O:12])[C:7]1[O:11][CH:10]=[CH:9][CH:8]=1.[CH:13](=[O:19])[CH:14]1[O:18][CH2:17][CH2:16][CH2:15]1>CCCCCCCCCCCCCCCC>[CH:9]1[CH:8]=[C:7]([CH:6]([OH:12])[C:13]([C:14]2[O:18][CH:17]=[CH:16][CH:15]=2)=[O:19])[O:11][CH:10]=1
Reactant: O=Cc1ccco1
Reactant: O=CC1CCCO1
Solvent: CCCCCCCCCCCCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccco1)C(O)c1ccco1

Procedure:
This has as a consequence that if we use stoichiometric ratios, which means 2 moles of furfural and 1 mol of acetone (since the acetone can react at both ends), between 16 and 37% of components with only 5 carbon atoms would be obtained that have a very limited interest as components for gasoline (App. Catal. B Environ. 2006, 66, 111-118). A second product with 8 carbon atoms which is usually one third of the mix appears in other conditions. This condensation product is hydrogenated to n-octane that does not have an interesting application in gasoline for having linear chain, or in diesel for the low molecular weight. To increase the selectivity to 85% with a yield of 71% the condensation has to be carried out in an aqueous phase, and the hydrogenation in hexadecane as a solvent at 120° C. which is a more expensive method (Appl. Catal. B Environ. 2006, 66, 111-118). The own authors realized the drawbacks caused by the selectivity and proposed as an alternative the hydrogenation of the furane ring to tetrahydrofurane since these derivatives are able to carry out an aldol condensation with themselves which would ensure a high selectivity. However, chemoselective hydrogenation of, e.g., furfural to tetrahydrofurfural in one step is still a challenge and is currently carried out in several stages. In any case, if a multi-stage method is accepted, molecules with a total of 10 carbon atoms can be obtained (Science 2005, 308, 1446-1450) the same as by furoin formation.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].[CH:19]#[C:20][CH2:21][CH3:22]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:19]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16])#[C:20][CH2:21][CH3:22]
Reactant: C#CCC
Reactant: NS(=O)(=O)c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC#Cc1ccccc1S(N)(=O)=O
Reaction time: 18 h

Procedure:
0.1 g of bis(triphenylphosphine)palladium(II) chloride, 0.05 g of copper iodide and 18.5 ml of triethylamine are added to a solution of 5 g of 2-iodobenzenesulfonamide in 70 ml of N,N-dimethylformamide. At room temperature, argon and 1-butyne are slowly introduced. After 18 hours the thin-layer chromatogram no longer shows any 2-iodobenzenesulfonamide. The dimethylformamide is evaporated off at 0.1 torr and 40°, and the residue is chromatographed on 300 g of silica gel (Merck ST 60, 40-63 μm). Methylene chloride is used as eluant. In that manner, after concentration of the product-containing fractions at 15 torr and 40°, white pulverulent 2-(but-1-yn-1-yl)-benzenesulfonamide is obtained: 1H-NMR (300 MHz, CDCl3): 8.0 (d, d, 1H); 7.35 (d, d, 1H); 7.29 (d, t, 1H); 7.23 (d, t, 1H); 5.13 (s, 2H); 2.32 (q, 2H); 1.18 (t, 3H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[N+:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[C-:19]>C1COCC1>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]2[O:14][CH:19]=[N:18][C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11][CH:10]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ncoc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (20 mL, 144 mmol) was added to a solution of 4-chlorobenzoyl chloride (8.4 g, 48 mmol) in THF (100 mL) at 0° C. Ethyl 2-isocyanoacetate (6.0 g, 53 mmol) was added dropwise and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column with ethyl acetate and hexanes as eluents to give the desired compound. MS (m/z) 252.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(#N)C>[Cl:8][C:6]1[N:7]=[C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Cl)nc(Cl)c2=O)c1
Reactant: CN1CCNCC1
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-n2cc(Cl)nc(N3CCN(C)CC3)c2=O)c1
Reaction time: 12 h

Procedure:
To a stirred solution of 3-(3,5-dichloro-2-oxo-1(2H)-pyrazinyl)-4-methyl-benzoic acid, methyl ester, (Example 107a, 250 mg) in acetonitrile (5 mL) was added 1-methyl-piperazine (0.2 mL). After 12 h, the reaction mixture was concentrated in vacuo. The residue was diluted with dichloromethane, washed with sat. aqueous NaHCO3, dried (MgSO4), filtered and the solvent removed to afford the subtitle compound. MS: APCI(+ve) 377 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:25](=[O:42])[N:26]([C:33]2[O:41][C:37]3=[CH:38][CH:39]=[CH:40][C:36]3=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[OH-].[Li+]>C1COCC1.CO.O>[O:41]1[C:37]2=[CH:38][CH:39]=[CH:40][C:36]2=[CH:35][CH:34]=[C:33]1[N:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:25]([CH:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)=[CH:17][CH:18]=1)[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[CH:5][CH:6]=1)=[O:42]
Reactant: COC(=O)c1ccc(CC(Cc2ccc(C3=CCCCC3)cc2)C(=O)N(c2ccccc2)c2ccc3cccc-3o2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CC(Cc2ccc(C3=CCCCC3)cc2)C(=O)N(c2ccccc2)c2ccc3cccc-3o2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the crude 4-[2-(4-Benzofuran-2-ylphenylcarbamoyl)-3-(4-cyclohex-1-enylphenyl)-propyl]-benzoic acid methyl ester from step e dissolved in 20 mL of THF/MeOH/H2O (3:1:1) was added lithium hydroxide (74 mg, 1.8 mmol) After stirring for 5 hrs at RT, the organic solvents were removed under vacuum and the reaction residue diluted further with water (25 mL). The aqueous mixture was made acidic with 1 N HCl and extracted with ethyl acetate. The ethyl acetate portion was then dried over Na2SO4 and concentrated under vacuum to afford 4-[2-(4-Benzofuran-2-ylphenylcarbamoyl)-3-(4-cyclohex-1-enylphenyl)-propyl]-benzoic acid which was carried on as is for the next step.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])(=O)OC.O.[NH2:30][NH2:31]>>[CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4]1[C:3]2=[N:30][N:31]=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH:19]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: COP(=O)(CC(=O)c1ccccc1C)OC
Reactant: NN
Solvent: O
Product: Cc1ccccc1-c1cc2c(nn1)[C@@]1(C)CC[C@@H]2C1(C)C

Procedure:
yellow gum. MS (ESI): 278.2 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, (2-Oxo-2-o-tolyl-ethyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.