Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:22])[CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]2[CH2:33][O:34][CH2:35][CH:29]2[CH2:28]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH:30]5[CH2:33][O:34][CH2:35][CH:29]5[CH2:28]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCCN1CCC2COCC2C1
Reactant: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCN1CCC2COCC2C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A mixture of 4-((4-bromo-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (225 mg, 0.62 mmol, 1 eq), 5-(3-chloropropyl)octahydrofuro[3,4-c]pyridine (151 mg, 0.74 mmol, 1.2 eq) and K2CO3 (171 mg, 1.24 mmol, 2 eq) in DMF (10 mL) was stirred at 80° C. overnight and cooled to room temperature. To this, CH2Cl2 (50 mL) was added. The mixture was washed with brine (20 mL×3) and water (20 mL×2), then dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a yellow solid (199 mg, 60.50%), HPLC: 98.32%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 531.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.69-1.73 (2H, m), 2.41-2.46 (3H, m), 2.64-2.66 (2H, m), 2.68-2.70 (3H, m), 2.75-2.82 (2H, m), 3.00-3.03 (3H, m), 3.06-3.10 (2H, m), 3.81-3.85 (2H, m), 4.23-4.27 (2H, m), 7.06-7.12 (1H, m), 7.21 (1H, s), 7.68-7.79 (2H, m), 7.87 (1H, s), 8.06-8.11 (1H, m), 8.65 (1H, s) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: CCc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[C:14]([CH:15]=O)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[CH:11]=2)[N:6]=1>O.C(O)C>[Cl:4][C:5]1[C:14]([CH:15]=[N:2][OH:3])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[CH:11]=2)[N:6]=1
Reactant: NO
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc2nc(Cl)c(C=NO)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
A solution of 6.5 g hydroxylamine hydrochloride in 25 ml water was added to a suspension of 18.7 g 2-chloro-6-methoxy-3-quinolinecarboxaldehyde in 500 ml 95% ethanol. The mixture was stirred at room temperature for two hours and then heated at reflux for three hours. The reaction mixture was cooled to 0° C., filtered, and the filtrate concentrated to a volume of 200 ml. The product separated from solution to give 16.3 g 2-chloro-6-methoxy-3-quinolinecarboxaldehyde oxime, m.p. 195° C. (decompn.).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]O)=[CH:18][CH:17]=1.S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][Cl:26])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl alcohol (6.8 g) in chloroform (100 ml) was added thionyl chloride (3.1 g), and the mixture was stirred for one hour at room temperature. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and then water, followed by drying (MgSO4). The solvent was distilled off to leave 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl chloride (6.5 g, 90%) as colorless needles, m.p.93°-94° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([C:38]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Br:1])[C:3]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=6)[CH2:14][CH2:13]5)=[C:4]4[N:9]=3)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: Brc1cnc2[nH]c(-c3ccc(Cn4cccn4)cc3)nc2c1N1CCN(Cc2ccncc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.039 g, 0.10 mmol) and EtOH (3.5 ml) was added 4-pyrazol-1-ylmethyl-benzaldehyde (0.024 g, 0.13 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.40 ml, 0.40 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (2 to 5%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.025 g, 48%); 1H-NMR (500 MHz, DMSO-d6) 2.63 (br s, 4H, piperazine N(CH2)2), 3.61 (s, 2H, NCH2pyridyl), 3.69 (br s, 4H, piperazine N(CH2)2), 5.42 (s, 2H, C6H4CH2N), 6.30 (t, J=2.0 Hz, 1H, pyrazole 4-H), 7.35 (d, J=8.3 Hz, 2H) and 8.14 (d, J=8.2 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.39 (d, J=5.9 Hz, 2H, pyridine 3-H, 5-H), 7.49 (d, J=1.7 Hz, 1H, pyrazole-H), 7.86 (d, J=2.2 Hz, 1H, pyrazole-H), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.54 (d, J=5.9 Hz, 2H, pyridine 2-H, 6-H), 13.50 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(CC)C(C)C)(C)C.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][S:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1)[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][S:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1)[C:23]([O:25][CH2:2][C:3]#[N:4])=[O:24])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNSc1ncccc1[N+](=O)[O-])C(=O)O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNSc1ncccc1[N+](=O)[O-])C(=O)OCC#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.2 %

Procedure:
Bromoacetonitrile (76 μl, 1.124 mmol) and N,N-diisopropylethylamine (196 μl, 1.124 mmol) were added to a solution of ((S)-2-((tert-butoxycarbonyl)amino)-6-(((3-nitropyridin-2-yl)thio)amino)hexanoic acid (Compound tk87) (150 mg, 0.375 mmol) in acetonitrile (6 ml), and the reaction solution was stirred at room temperature for 5 hours. Bromoacetonitrile (49 μl, 0.413 mmol) was further added and the mixture was stirred at room temperature for 1 hour to complete the reaction. The reaction mixture was concentrated under reduced pressure using an evaporator, and the residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-6-(((3-nitropyridin-2-yl)thio)amino)hexanoate (Compound tk88) (152 mg, 92%).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:24][NH:25][C:26]([C:28]2[C:29]([CH3:38])=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][N:32]=3)=[O:27])[CH:16]=[CH:17][C:18]=1[CH2:19][O:20][CH2:21][CH2:22][OH:23].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:23][CH2:22][CH2:21][O:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([CH2:24][NH:25][C:26]([C:28]3[C:29]([CH3:38])=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][N:32]=4)=[O:27])=[CH:14][C:13]=2[F:12])(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Cc1nc2ncccc2cc1C(=O)NCc1ccc(COCCO)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCc2ccc(CNC(=O)c3cc4cccnc4nc3C)cc2F)cc1
Reaction time: 2 h

Procedure:
25 mg tosylchloride (0.13 mmol) was added to a solution of 40 mg N-[[3-fluoro-4-(2-hydroxyethoxymethyl)phenyl]methyl]-2-methyl-1,8-naphthyridine-3-carboxamide (0.11 mmol), 23 μl diisopropylethylamine (6.13 mmol) and 13 mg DMAP (0.11 mmol) in 1.0 ml CH2Cl2 at room temperature. The solution was stirred for 2 h. The reaction mixture was placed directly on a SiO2 column and purified by flash chromatography (CH2Cl2/MeOH 50:1). Gave 52 mg (90%).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[C:12]2[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[C:9]([F:16])=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.Cl.[CH3:18]O>>[ClH:1].[NH2:2][C@H:3]1[C:12]2[CH:11]=[C:10]([C:13]([O:15][CH3:18])=[O:14])[C:9]([F:16])=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: CO
Reactant: N[C@@H]1CCCc2cc(F)c(C(=O)O)cc21
Agent: Cl
Product: COC(=O)c1cc2c(cc1F)CCC[C@H]2N
Yield: 95 %

Procedure:
Step-1: (R)-8-Amino-3-fluoro-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride (commercially obtainable from NetChem Company (order no. 573545)) (2.035 mmol, 1 eq.) was added to a solution of HCl in methanol (1.25 M, 15 eq.) and the resulting mixture was heated to reflux for 16 h. The solvent was concentrated in vacuo, and the residue was dissolved in acetone (5 ml) and diethyl ether (30 ml) was added. The white solid was collected by filtration, washed with diethyl ether and dried in vacuo. Yield: 95%
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[C:3]1=[CH:26][CH2:27][OH:28].C(N(CC)CC)C.[H][H]>CO.[Pd]>[CH3:1][C:2]1([CH3:29])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[CH:3]1[CH2:26][CH2:27][OH:28]
Reactant: [H][H]
Reactant: COc1ccc2c(c1)C(=CCO)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(CCO)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2

Procedure:
2,2-Dimethyl-1-(2-hydroxyethylidene)-7-methoxy-3-(N-methyl-p-toluenesulphonamido)-1,2,3,4-tetrahydronaphthalene (15.5 g), dissolved in 250 ml of methanol, containing 2.2 ml of triethylamine, is submitted to catalytic hydrogenation, at atmosphere pressure and room temperature, the catalyst being 2.3 g 5% palladium on charcoal. The calculated amount of hydrogen is taken up within one hour. The catalyst is removed by filtration and the solvent by evaporation in vacuo. The residue is dissolved in chloroform and the solution is freed from basic material by means of washing with dilute hydrochloric acid and water, respectively. The dried solution is then concentrated in vacuo leaving a mixture containing two stereoisomers of the desired product. This mixture is suitable for further elaboration as described in example 13.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[C:15]1([C:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:22][CH2:23][CH2:24][CH2:25]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][N:3]([CH3:2])[CH2:25][CH2:24][CH2:23][NH:22][C:21]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CNCCOc1ccccc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OCCN(C)CCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 15.5 h

Procedure:
8.05 g (0.0370 mol) of N-methyl-2-(2-methoxyphenoxy) ethylamine hydrochloride, 15.5 g (0. 0407 mol) of N-triphenylmethyl-3-bromopropylamine, (0.0925 mol) of potassium carbonate and 75 ml of N,N-dimethylformamide are introduced, under argon, into a 500 ml, three-necked, round-bottomed flask. The mixture is stirred for 15.5 h at 90° C. The reaction mixture is treated with a mixture of water and ice and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and concentrated under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=O)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:37][CH:38]([NH2:45])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>C(OCC)(=O)C>[CH3:37][CH:38]([NH:45][C:16](=[O:18])[CH:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:20][CH3:21])[CH:11]=1)[CH3:19])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCC(C)N
Reactant: COc1cc(C(C)C(=O)O)ccc1OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCCCCCC(C)NC(=O)C(C)c1ccc(OCc2ccccc2)c(OC)c1
Reaction time: 0.33 h

Procedure:
A solution of 2-(4-benzyloxy-3-methoxyphenyl)propionic acid (5.0 g, 17.5 mmoles) and 4-methylmorpholine (2.0 mL, 17.5 mmoles) in ethyl acetate (170 mL) at 0° C. was treated with isobutyl chloroformate (2.26 mL, 17.5 mmoles). The resulting white slurry was stirred for 20 minutes. A solution of racemic 2-octylamine (2.7 g, 21 mmoles) in ethyl acetate (10 mL total solution) was added to the suspension which was then stirred for 3 hours. The mixture was extracted with 1M hydrochloric acid (3×50 mL), with a saturated sodium bicarbonate solution (3×50 mL), with brine (1×50 mL) and dried over magnesium sulfate. The ethyl acetate was rotary evaporated affording N-2-octyl-2-(4-benzyloxy-3-methoxyphenyl)proprionamide as a white solid which was crystallized from ether/methylene chloride to give 4.55 g. This racemic mixture of diastereomers was separated by silica gel chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH:18]4[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]4)[CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.I.CS[C:24]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)=[NH:25]>C(O)C.[Pd]>[N:15]12[CH2:20][CH2:19][CH:18]([CH2:17][CH2:16]1)[CH:13]([C:8]1[C:7]3[C:11](=[CH:12][C:4]([NH:1][C:24]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[NH:25])=[CH:5][CH:6]=3)[NH:10][CH:9]=1)[CH2:14]2
Reactant: CSC(=N)c1cccs1
Reactant: O=[N+]([O-])c1ccc2c(C3=CN4CCC3CC4)c[nH]c2c1
Agent: [Pd]
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2c(C3CN4CCC3CC4)c[nH]c2c1)c1cccs1
Temperature: 25 °C
Reaction time: 36 h
Yield: 76.9 %

Procedure:
Compound 109 (0.4 g, 1.485 mmol) in dry ethanol (10 mL) was treated with Pd—C (˜0.05 g), purged with hydrogen gas and stirred for 36 h at room temperature under hydrogen atm (balloon pressure). The reaction was filtered through celite bed and washed with ethanol (2×5 mL). The combined ethanol layer was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.84 g, 2.970 mmol) at room temperature and stirred for over night (14 h). The solvent was evaporated, crude was diluted with sat. NaHCO3 solution (25 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 112 (0.4 g, 77%) as a solid. mp 144-146° C.; 1H NMR (DMSO-d6) δ 1.20-1.28 (m, 1H), 1.56-1.74 (m, 3H), 2.62-2.72 (m, 1H), 2.79-2.92 (m, 3H), 3.09-3.34 (m, 4H), 6.30 (s, 2H), 6.53 (d, 1H, J=8.4 Hz), 6.79 (s, 1H), 7.07-7.10 (m, 2H), 7.38 (d, 1H, J=8.4 Hz), 7.58 (d, 1H, J=4.5 Hz), 7.72 (d, 1H, J=3.0 Hz), 10.61 (s, 1H); ESI-MS (m/z, %): 351 (MH+, 38), 176 (100); ESI-HRMS calculated for C20H23N4S (MH+), calculated: 351.1637; observed: 351.1637.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24](O)=[O:25])[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][O:29][C:30](=[O:40])[CH:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:32]>CN(C)C=O>[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:32][C:24](=[O:25])[C@H:12]([CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(N[C@H](C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O
Yield: 82.2 %

Procedure:
The process of Example 1 was repeated except that 357 mg (1.00 mmol) of N-benzyloxycarbonyl-(β-benzyl)-L-aspartic acid, and 431 mg (2.00 mmol) of D,L-phenylalanine methyl ester hydrochloride were used. As a result, 426 mg (yield of 82.1%) of N-benzyloxycarbonyl-(β-benzyl)-L-aspartyl-L-phenylalanine methyl ester having an [α]D25 = -12.5 (C=1.0 dimethylformamide) were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([CH2:21][CH2:22][NH:23]C(OCC[Si](C)(C)C)=O)[N:18]=[CH:17]1)=[O:12].[ClH:33]>C(#N)C>[ClH:33].[ClH:33].[ClH:33].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([CH2:21][CH2:22][NH2:23])[N:18]=[CH:17]1)=[O:12]
Reactant: C[Si](C)(C)CCOC(=O)NCCc1cn(CCNC(=O)CCSSc2ccccn2)cn1
Agent: Cl
Solvent: CC#N
Product: NCCc1cn(CCNC(=O)CCSSc2ccccn2)cn1

Procedure:
6.6 mg (13.4 μmol) of compound IV is hydrolyzed for 2.5 hours in 0.5 ml of acetonitrile containing 76 μl of conc. HCl, to thus form compound V. The pH of the reaction solution is raised to 7.2 by addition of 500 μl of 0.1M phosphate buffer and solid NaHCO3. Gaseous nitrogen is bubbled through the solution. Then the solution is added to a slurry of 100 mg of thiopropyl Sephadex® G-50 containing 11.4 μmol of SH groups in 0.1M phosphate buffer pH 7.2. The mixture is agitated in a rotary mixer for 20 hours at room temperature. The gel is transferred to a Pasteur pipette. The reaction mother liquor is allowed to drain off, and the gel is washed with 6×1.5 ml of 0.05M phosphate buffer pH 7.4. The amount of thiopyridone that has formed is UV-analyzed in the reaction mother liquor+wash liquors. An amount of 4.45 μmol thiopyridone is detected, indicating that 4.45 μmol of compound V has been coupled to 100 mg of dry beads.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC.[F-].[K+]>C1(C)C=CC=CC=1>[N:4]1[CH:3]=[C:2]([C:16](=[O:18])[CH3:17])[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: Brc1cnc2n1CCCC2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)c1cnc2n1CCCC2
Temperature: 120 °C
Reaction time: 8 h

Procedure:
142 mg of the 3-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [44-2] was dissolved in 2.5 mL of toluene, 81.6 mg of tetrakis triphenylphosphine palladium (0) and 477 μL of tributyl(1-ethoxyvinyl)tin were added, and the mixture was stirred overnight at 120° C. The reaction mixture was cooled back to room temperature to add 10% aqueous solution of potassium fluoride, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous solution of potassium fluoride and with saturated brine in the subsequent order, and then was dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then the purification by silica gel column chromatography was carried out. The obtained compound was dissolved in 2 mL of chloroform, 200 μL of 10% hydrochloric acid-methanol solution was added, and the mixture was stirred for 40 minutes. The liquid was basified by adding a saturated aqueous solution of sodium hydrogen carbonate, and was extracted with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative thin-layer chromatography to obtain 62.2 mg of 1-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)ethanone [44-3] as a pale yellow oily product.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH3:33])[CH:27]=1)([CH3:25])=[O:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([P:23]([CH3:25])([CH3:22])=[O:24])=[CH:27][C:28]=2[CH3:33])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Reactant: Cc1cc(P(C)(C)=O)ccc1N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1cc(P(C)(C)=O)ccc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 4-(Dimethylphosphoryl)-2-methylaniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:16]O.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:19][CH2:16][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:2]=1[Cl:1]
Reactant: OCc1ccc(OCc2ccccc2)cc1Cl
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cc(OCc2ccccc2)ccc1CBr
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
To a solution of {2-chloro-4-[(phenylmethyl)oxy]phenyl}methanol (2.08 g, 8.36 mmol) in DCM (20 ml) under nitrogen in an ice-water bath was added a solution of phosphorus tribromide (0.83 ml, 8.80 mmol, Aldrich) in DCM (10 ml). The solution was allowed to warm to ambient temperature and stirred for 1.5 h. The reaction mixture was poured onto ice-water (70 ml) and saturated aqueous sodium hydrogen carbonate (30 ml). The mixture was diluted with DCM (50 ml), and the phases separated. The aqueous extract was washed with dichloromethane (20 ml). The combined organic extracts were washed with water (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to give 1-(bromomethyl)-2-chloro-4-[(phenylmethyl)oxy]benzene as white solid (2.48 g).