Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:34])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:33])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:32])[C@H:22]([CH3:31])[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:27]([O:26][C:24]([NH:23][C@H:22]([C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:34])=[O:8])=[O:33])=[O:32])[CH3:31])=[O:25])([CH3:28])([CH3:29])[CH3:30]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Yield: 99.8 %

Procedure:
N-t-butyloxycarbonyl-L-alanyl-L-prolyl-L-proline benzylester (5.0 g, 10.6 m mole) was dissolved in methanol (100 ml) and hydrogen gas was passed through the solution in the presence of the palladium carbon as a catalyst for 3 hours. The catalyst was removed by filtration and the solvent was distilled off under reduced pressure. Thus obtained residue was dissolved in water and the solution was freeze-dried to give N-t-butyloxycarbonyl-L-alanyl-L-prolyl-L-proline (4.04 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([O:23][CH2:24][CH3:25])(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17].C(N=C=NC(C)C)(C)C>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:16]2([OH:17])[CH:18]=[CH:19][CH:20]=[CH:21][CH:15]2[C:14]([O:23][CH2:24][CH3:25])=[O:22])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCCc1ccccc1
Reactant: CCOC(=O)c1ccccc1O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CCOC(=O)C1C=CC=CC1(O)C(=O)CCCCc1ccccc1
Reaction time: 18 h

Procedure:
To a stirred solution of 1.07 g of 5-phenylvaleric acid and 60 mg of N,N-dimethylaminopyridine in 20 ml of dichloromethane is added 0.75 ml of ethyl salicylate, followed by 0.95 ml of diisopropyl carbodiimide. After 18 hours, the mixture is concentrated under reduced pressure, and the residue triturated with ether. The organic phase is washed with aq. sodium bicarbonate and brine, dried (magnesium sulfate), and concentrated under reduced pressure. Flash chromatography on silica with 10% ethyl acetate in hexane affords 1.60 g of the title product as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:15]
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(N)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
To a stirred solution of 3-methyl-4-phenoxynitrobenzene (2) (548 g, 2.39 moles, 1.0 eq.) in methanol (5 L) was added 10% Pd/C (100 g, 50% wet, 46.98 mmol, 0.02 eq.). Then the reaction mixture was stirred under a hydrogen atmosphere (60-80 psi) for 15-16 hours at room temperature in a 2 gallon Parr hydrogenator. The progress of the reaction was monitored by TLC (50% ethyl acetate in hexanes, sm Rf=0.69, pr Rf=0.47, UV visible). Then the reaction mixture was filtered through Celite, and the solid was washed with excess methanol. The filtrate was concentrated under reduced pressure to give 3-methyl-4-phenoxyaniline as a pale brown viscous liquid (451.0 9, 95%). The 3-methyl-4-phenoxyaniline was found to be pure by 1H and 13C NMR spectra, and used as such in the next reaction.
Reaction SMILES: [H-].[Na+].C(=O)=O.CO.[Br:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[N:13][CH:14]=1.Br[CH2:19][CH2:20][O:21][CH2:22][CH2:23]Br>C1COCC1>[Br:8][C:9]1[CH:10]=[C:11]([C:15]2([C:16]#[N:17])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:12]=[N:13][CH:14]=1
Reactant: BrCCOCCBr
Reactant: N#CCc1cncc(Br)c1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#CC1(c2cncc(Br)c2)CCOCC1
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
Under argon, NaH (60% in mineral oil, 0.497 g, 12.4 mmol) is added into THF (10 mL). The reaction mixture is cooled on a bath of dry ice/CH3OH. A solution of (5-bromo-pyridin-3-yl)-acetonitrile (1.0 g, 5.0 mmol) and 2-bromoethyl ether (0.719 mL, 5.15 mmol) in THF (4.5 mL) is added dropwise. The reaction is stirred for 30 min. The dry ice/MeOH bath is removed and the mixture is stirred at room temperature for 14 hrs. The reaction is quenched by slow addition of MeOH (5 mL). The mixture is then concentrated. The resulting crude product is purified by normal phase chromatography using 0-3% MeOH in DCM as the gradient to afford 4-(5-bromo-pyridin-3-yl)-tetrahydro-pyran-4-carbonitrile (1.07 g, 79% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][N:10]=2)[CH:7]=1.[C:19]([O:23][C:24]([NH:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][CH3:18])=[N:9][N:10]=3)[CH:7]=2)[CH:30]=[CH:29][CH:28]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1ccccc1-c1nnc2ccc(Br)cn12
Reactant: CC(C)(C)OC(=O)Nc1cccc(B(O)O)c1
Product: COc1ccccc1-c1nnc2ccc(-c3cccc(NC(=O)OC(C)(C)C)c3)cn12

Procedure:
The title compound was prepared from 6-bromo-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine and 3-(tert-butoxycarbonylamino)phenylboronic acid using a procedure similar to those described for the synthesis of Example 22, and was isolated as yellow solids (78 mg, 22.0% yield). MS: m/z 417.2 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:35][O:36][CH:37]1[CH2:40][NH:39][CH2:38]1.C(Cl)(Cl)Cl>CN(C=O)C>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:39]4[CH2:40][CH:37]([O:36][CH3:35])[CH2:38]4)[CH:3]=3)=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: COC1CNC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(N4CC(OC)C4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-methoxy-azetidine hydrochloride in DMF. [α]D20=+42.5° (c=0.44, CHCl3), ES-MS m/e (%): 457 (M+H+, 100).
Reaction SMILES: [BrH:1].C([CH:6]1[CH:11]([OH:12])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:9]([CH2:20][OH:21])[CH2:8][N:7]1CC1C=CC=CC=1)(C)(C)C>[Pd].CO>[BrH:1].[OH:21][CH2:20][CH:9]1[CH2:8][NH:7][CH2:6][CH:11]([OH:12])[CH:10]1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1
Reactant: CC(C)(C)C1C(O)C(c2ccc(O)cc2)C(CO)CN1Cc1ccccc1
Agent: [Pd]
Agent: Br
Solvent: CO
Product: OCC1CNCC(O)C1c1ccc(O)cc1

Procedure:
In an analogous manner to that described in Example 2(e), by catalytic hydrogenation at atmospheric pressure using a 10% palladium-charcoal catalyst in methanol from tert-butyl (3RS,4RS,5SR)-1-benzyl-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidin-3-ol hydrobromide there was obtained (3RS,4RS,5SR)-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidin-3-ol hydrobromide as a colourless foam; MS: 224 (M+H)+.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClCCCl.C1C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: ClCCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (0.6 g) in anhydrous 1,2-dichloroethane (12 ml) was added rhodium(II) acetate (2 mg) under refluxing. After refluxing for 20 minutes, the reaction mixture was cooled and evaporated in vacuo to give a residue. The residue was dissolved in anhydrous benzene (10 ml) and then evaporated. This operation was repeated once again and the residue was dried in vacuo to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate. The compound obtained above was dissolved in anhydrous acetonitrile (15 ml) and cooled to 0° C. under an atmosphere of nitrogen. To this solution were added N,N-diisopropyl-N-ethylamine (0.32 ml) and diphenyl phosphorochloridate (0.33 ml) successively, and the solution was stirred at 0° C. for 40 minutes. To the resulting solution were added dropwise a solution of (2S,4S)-4-mercapto-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.76 g) in anhydrous acetonitrile (3 ml) and N,N-diisopropyl-N-ethylamine (0.32 ml) with stirring at 0°-2° C., and the stirring was continued at the same temperature for 2 hours. Ethyl acetate (50 ml) was added to the reaction mixture. The mixture was washed twice with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (5:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-4-methyl-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.81 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:13][N:12]=[C:11]([NH:27][C@H:28]3[CH2:33][CH2:32][C@@H:31]([CH3:34])[CH2:30][CH2:29]3)[N:10]=2)[CH2:3][CH2:2]1.Cl[C:36]([O:38][CH3:39])=[O:37]>>[CH3:34][C@@H:31]1[CH2:30][CH2:29][C@H:28]([NH:27][C:11]2[N:10]=[C:9]([O:8][CH2:7][CH:4]3[CH2:3][CH2:2][N:1]([C:36]([O:38][CH3:39])=[O:37])[CH2:6][CH2:5]3)[C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:13][N:12]=2)[CH2:33][CH2:32]1
Reactant: COC(=O)Cl
Reactant: C[C@H]1CC[C@@H](Nc2ncc(-c3ccc(N4CCOCC4)cc3)c(OCC3CCNCC3)n2)CC1
Product: COC(=O)N1CCC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)CC1

Procedure:
Using the procedure of Example 1 Step 5, 4-((piperidin-4-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine was reacted with methyl chloroformate to provide the title compound. 1H NMR (CDCl3, 400 MHz) 8.07 (s, 1H), 7.37 (d, 2H), 6.93 (d, 2H), 5.19 (sb, 1H), 4.19 (d, 2H), 4.07 (m, 3H), 3.88 (m, 4H), 3.69 (s, 3H), 3.20 (m, 4H), 2.77 (m, 2H), 1.97-1.57 (m, 11H), 1.26 (m, 3H), 0.94 (d, 3H); MS (ESI) m/z: Calc: 523.3 (M+). Found. 524.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23]CC2C=CC=CC=2)=[CH:12][CH:11]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:14][CH:15]=1
Reactant: COC(=O)CCCCCOc1ccc(NC(=O)CCCCCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCOc1ccc(NC(=O)CCCCCO)cc1
Reaction time: 20 h
Yield: 62.8 %

Procedure:
6-[4-(6-Benzyloxyhexanoylamino)phenoxy]hexanoic acid methyl ester 80 (10 g, 22.67 mmol) was dissolved in methanol (100 ml) in a pressure vessel, palladium on carbon (5%, 6 grams) added, and the mixture stirred under a hydrogen atm. (4 Kg) for 20 hrs. Catalyst was removed by filtration and methanol distilled off. Crude 81 was purified by column chromatography on silica gel using chloroform as eluant to give pure 81 (5 g, 62.8%) as a white powder. M.p: 73-75.5°
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[CH:5]2.[NH:26]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([N:26]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]3)=[O:25])[N:21]=1)=[CH:5]2
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: OC1CCNC1
Product: O=C(C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1)N1CCC(O)C1
Yield: 40 %

Procedure:
The compound (40 mg, 0.11 mmol) prepared in Example 27 and 3-pyrrolidinol instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (19 mg, Yield 40%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]2=[N:8][CH:7]=1)CCC.Br[C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH:38]=[CH:37][CH:36]=[CH:35]2)=[N:32][CH:33]=1>>[N:34]1([C:31]2[CH:30]=[CH:29][C:28]([C:6]3[N:10]4[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[N:14][C:9]4=[N:8][CH:7]=3)=[CH:33][N:32]=2)[CH:38]=[CH:37][CH:36]=[CH:35]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1ccc(-n2cccc2)nc1
Product: FC(F)(F)c1ccn2c(-c3ccc(-n4cccc4)nc3)cnc2n1

Procedure:
3-Tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine was reacted with 5-bromo-2-(pyrrol-1-yl)pyridine by the method of Example 1 to afford 3-[2-(1H-pyrrol-1-yl)pyridin-5-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 6.42 (2H, m), 7.28 (1H, d, J 8), 7.52 (1H, dd, J 8 and 1), 7.58 (2H, m), 7.92 (1H, dd, J 8 and 2), 8.14 (1H, s), 8.64 (1H, dd, J 2 and 1), 8.74 (1H, d, J 8), m/z (ES+) 329, 330 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:28])[N:8]([CH:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5]=2[NH:4][N:3]=1.CCCCCC.C(O)C.C(NCC)C>>[NH2:1][C:2]1[C:6]2[C:7](=[O:28])[N:8]([C@@H:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[CH:13][N:12]=3)[C:5]=2[NH:4][N:3]=1
Reactant: CC(C)C(C)n1cc(-c2ccc(N3CCOCC3)cn2)c2[nH]nc(N)c2c1=O
Solvent: CCCCCC
Solvent: CCO
Solvent: CCNCC
Product: CC(C)[C@@H](C)n1cc(-c2ccc(N3CCOCC3)cn2)c2[nH]nc(N)c2c1=O
Yield: 47.8 %

Procedure:
Racemic 3-amino-5-(3-methylbutan-2-yl)-7-(5-(morpholin-4-yl)pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Example 116 (90 mg) was resolved by HPLC (column: CHIRALCEL OJ, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol/diethylamine=700/300/1(v/v/v)) to give the title compound (43 mg) having a shorter retention time.
Reaction SMILES: I[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]1([C:12](Cl)=[O:13])[CH2:11][CH2:10]1>C1C=CC=CC=1.CC(N(C)C)=O.C(OCC)(=O)C.[Cu].[Zn].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>[CH:9]1([C:12](=[O:13])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:11][CH2:10]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)CCI
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)CCC(=O)C1CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A mixture of ethyl 3-iodopropanoate (8 g, 35 mmol) and zinc-copper (4.5 g, 70 mmol) in a mixture of benzene (80 mL) and DMA (8 mL) was heated at 60° C. for 4.5 hours under N2. Pd(PPh3)2Cl2 (1.2 g, 1.8 mmol) was added, followed by addition of cyclopropanecarbonyl chloride (3.7 g, 35 mmol). The mixture was stirred at 60° C. for another 30 minutes. The reaction mixture was diluted with ethyl acetate (300 mL), and washed with 1N HCl (50 mL), satd aq NaHCO3 (80 mL) and brine (30 mL). The organic layer was dried over Na2SO4 and concentrated to afford the ethyl 4-cyclopropyl-4-oxobutanoate (4.2 g), which was used for next step directly without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.Cl.[CH3:17][C:18]1[CH:29]=[CH:28][C:21]([CH2:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:25]1[CH2:26][CH2:27][CH:23]([CH2:22][C:21]2[CH:20]=[CH:19][C:18]([CH3:17])=[CH:29][CH:28]=2)[CH2:24]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: Cc1ccc(CC2CCNC2)cc1
Agent: Cl
Product: Cc1ccc(CC2CCN(C(=O)c3cnoc3-c3ccccc3Cl)C2)cc1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(4-methylbenzyl)pyrrolidine hydrochloride (12.7 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (8.4 mg). Calcd for C22H21N2O2: 380.1292, found 380.1296.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:33][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:15]([S:18]([CH:21]([CH3:22])[CH3:23])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)C(C)C
Reactant: NC1CCCC1
Product: CC(C)S(=O)(=O)C(C#N)=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCCC1
Yield: 99 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-methylsulfanyl-2-propenenitrile (0.500 g, 1.16 mmol) was stirred in cyclopentylamine (2 ml) for 24 h at 80° C. under nitrogen in a sealed flask. Work up as described in Example 40, 2) gave 540 mg (99%) of the title compound as white crystals. Mp 172-173° C. 1H NMR (200 MHz, CDCl3): δ=1.41 (d, 6H), 1.40-1.57 (m, 4H), 1.74-1.93 (m, 4H), 3.25 (heptet, 1H), 3.56 (m, 1H), 7.54 (s, 2H), 7.67 (s, 1H), 7.94 (br s, 1H), 9.22 (br s, 1H)
Reaction SMILES: [CH2:1]([C:5]([CH3:7])=[O:6])[CH:2]([CH3:4])[CH3:3].[C:8]([OH:13])(=O)[C:9](O)=O>C(O)(=O)C>[CH:1]1[C:5]([OH:6])=[CH:7][CH:8]=[CH:3][C:2]=1[CH3:4].[CH:9]1[C:8]([OH:13])=[CH:5][CH:1]=[C:2]([CH3:4])[CH:3]=1
Reactant: CC(=O)CC(C)C
Reactant: O=C(O)C(=O)O
Solvent: CC(=O)O
Product: Cc1ccc(O)cc1
Product: Cc1cccc(O)c1

Procedure:
To a mixture of 59.3 g of the polyphenol compound obtained in Referential Example 1, 133.2 g of m-cresol, 118.0 g of p-cresol, 250 g of methyl isobutyl ketone, 37.0 g of 11% aqueous solution of oxalic acid and 85 g of 90% acetic acid was dropwise added 135.9 g of 37% aqueous solution of formaldehyde with stirring at 95° C. over a period of one hour. After the addition, the resulting mixture was allowed to react at the same temperature as above for 15 hours. The reaction mixture was washed with water and dehydrated by azeotropic distillation to obtain a solution of a novolak resin in methyl isobutyl ketone. As measured by GPC, the novolak resin had a polystyrene-converted weight average molecular weight of 4,571.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:8]([CH2:23][CH2:24][OH:25])[CH2:7][CH2:6]2.C1N=CN([C:31]([N:33]2C=N[CH:35]=[CH:34]2)=[O:32])C=1.N[C:39]1[C:48]2[C:43](=[CH:44]C=C[CH:47]=2)[N:42]=[CH:41][CH:40]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.O.CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:8]([CH2:23][CH2:24][O:25][C:31](=[O:32])[NH:33][C:34]1[C:35]3[C:41](=[CH:40][CH:39]=[CH:48][CH:47]=3)[N:42]=[CH:43][CH:44]=1)[CH2:7][CH2:6]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc2c(cc1OC)C(CCc1ccccc1)N(CCO)CC2
Reactant: Nc1ccnc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C(CCc1ccccc1)N(CCOC(=O)Nc1ccnc3ccccc13)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(6,7-dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethanol (example 113.1, 29.7 mg, 0.087 mmol) in THF (1 mL) is added CDI (28.2 mg, 0.174 mmol, 2.0 eq). The reaction mixture is stirred at rt for 3 h, and then 4-amino-quinoline (example C3, 14 mg, 0.1 mmol) is added. To the resulting solution is added in a single portion NaHMDS (2 M in THF, 218 μL, 0.44 mmol). The reaction mixture is stirred at rt for 30 min, then H2O/AcOH (9:1, 0.4 mL) is added. The reaction mixture is evaporated and the residue purified by preparative HPLC to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[S:16]([N:19]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[CH3:31])[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])=[O:17].[Cu][C:33]#[N:34]>CN1CCCC1=O>[C:33]([C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[S:16]([N:19]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[CH3:31])[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])=[O:17])#[N:34]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2Cl)c(C)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2C#N)c(C)c1
Temperature: 220 °C

Procedure:
To a solution of 2-chloro-N-(2,4-dimethylphenyl)-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (200 mg, 0.429 mmol) in N-methyl-2-pyrrolidone (NMP) (2 mL) was added copper(I) cyanide (77 mg, 0.858 mmol). The reaction vessel was sealed and heated by microwaves (Biotage Initiator) to 220° C. for 2 hours. After cooling the reaction LCMS analysis showed some evidence of the desired product. The reaction was reheated by microwaves to 220° C. for an additional 6 hours. The reaction was slowly and carefully quenched with dilute HCl (5 mL) and DCM (5 mL). The mixture was passed through a hydrophobic frit and the organic layer collected and concentrated in vacuo to give a brown oil. The crude was purified by mass directed autoprep (ammonium carbonate modifier). The appropriate fractions were evaporated in vacuo to give the required product, 56 mg. LCMS [LCMS2] Rt 1.47 min, m/z (ES+) 457 (M+H).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1.C([O:18]C([NH:21][N:22]=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][CH:25]=1)=O)(C)(C)C.N1C=CC=CC=1C1C=CC(C=NN)=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[CH:28]=[CH:29][C:24]([CH:23]=[N:22][NH2:21])=[CH:25][CH:26]=1.[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][C:1]([CH:13]=[O:18])=[CH:2][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN=Cc1ccc(-c2ccccn2)cc1
Reactant: Cc1ccc(-c2ccccn2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: NN=Cc1ccc(-c2ccccn2)cc1
Product: O=Cc1ccc(-c2ccccn2)cc1

Procedure:
The present inventors have found that 4-(pyridin-2-yl)benzaldehyde can be produced economically by reacting a salt of 2-(4-bromomethylphenyl)pyridine, 2-(4-dibromomethylphenyl)pyridine or a salt thereof, all of which being novel compounds, with hexamethylenetetramine and water, and further that a salt of 2-(4-bromomethylphenyl)pyridine, 2-(4-dibromomethylphenyl)pyridine and a salt thereof can be obtained by reacting a salt of 2-(4-tolyl)pyridine with a brominating agent. In addition, they have found that N-(tert-butoxycarbonyl)-N'-[4-(pyridin-2-yl)phenylmethylidene]hydrazine can be produced more economically and easily by reacting 4-(pyridin-2-yl)benzaldehyde hydrazone with di-tert-butyl dicarbonate, and that 4-(pyridin-2-yl)benzaldehyde hydrazone can be obtained from 4-(pyridin-2-yl)benzaldehyde.