Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[O:2]=[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH2:16]([CH:10]([C:3](=[O:2])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(=O)C(Cc1ccccc1)C(=O)OCC
Yield: 38.2 %

Procedure:
Under argon, and at room temperature, 1.7 g (74.18 mmol) of sodium are dissolved in 75 mL of anhydrous EtOH. 13.5 mL (74.2 mmol) of diethyl 3-oxopentanedioate and then 8.8 mL (74.2 mmol) of benzyl bromide are then added dropwise, at room temperature. The medium is then refluxed for 3 hours, concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 20% EtOAc. 8.29 g of diethyl 2-benzyl-3-oxopentanedioate are obtained in the form of a translucent oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:24])[N:11]([CH3:23])[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:25][O:26][C:27]1[CH:44]=[CH:43][C:30]([CH2:31][N:32]2[C:36]3=[N:37][CH:38]=[CH:39][C:40](Cl)=[C:35]3[C:34]([CH3:42])=[N:33]2)=[CH:29][CH:28]=1.CC([O-])(C)C.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:24])[N:11]([CH3:23])[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:40]1[CH:39]=[CH:38][N:37]=[C:36]2[N:32]([CH2:31][C:30]3[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:44][CH:43]=3)[N:33]=[C:34]([CH3:42])[C:35]=12
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Reactant: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(O)c(F)c2)c1=O
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(-c5cnc(Nc6ccc(F)cc6)n(C)c5=O)cc4F)ccnc32)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
To a mixture of 5-(3-fluoro-4-hydroxyphenyl)-2-(4-fluorophenylamino)-3-methylpyrimidin-4(3H)-one (25.2 mg, 0.077 mmol) and 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (20 mg, 0.070 mmol) dissolved in DMF (0.5 mL), added KOtBu (0.077 ml, 0.077 mmol) 1M solution in THF, and potassium carbonate (10.6 mg, 0.077 mmol). The mixture was stirred at 110° C. overnight. Cooled to room temperature and partitioned between EtOAc (15 mL) and water (20 mL). The organic layer was dried with brine, Na2SO4, and evaporated to afford 27 mg of crude product. Purified by silica gel column chromatography (Biotage 12M) eluting with 5% MeOH/EtOAc to afford desired product as white solid (4.6 mg, 11%). LRMS (APCI pos) m/e 581.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:20])[C:10](=[O:19])[NH:11][C:12]=2C(O)=O)[C:7]1=[O:21].N1C2C(=CC=CC=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:20])[C:10](=[O:19])[NH:11][CH:12]=2)[C:7]1=[O:21]
Reactant: O=C(O)c1[nH]c(=O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Solvent: c1ccc2ncccc2c1
Product: O=C1c2c(c[nH]c(=O)c2O)CCN1Cc1ccc(F)c(Cl)c1
Temperature: 190 °C

Procedure:
A mixture of 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylic acid (0.30 g, 0.82 mmol) and quinoline (0.11 g, 0.82 mmol) was heated at 190° C. for 2.5 hours. The product mixture was cooled to room temperature and triturated with diethyl ether. The solid precipitated was filtered, and was subjected to preparative reverse phase HPLC purification. Collection and lyophilization of appropriate fractions provide the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[S:6](=[O:8])(=[O:7])[C@@H:5]2[C:9](Br)(Br)[C:10](=[O:11])[N:4]2[C@H:3]1[C:14]([OH:16])=[O:15].C(=O)(O)[O-].[Na+]>[Pd].C(OCC)(=O)C>[CH3:1][C:2]1([CH3:17])[S:6](=[O:7])(=[O:8])[C@@H:5]2[CH2:9][C:10](=[O:11])[N:4]2[C@H:3]1[C:14]([OH:16])=[O:15]
Reactant: CC1(C)[C@H](C(=O)O)N2C(=O)C(Br)(Br)[C@H]2S1(=O)=O
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(C)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O
Reaction time: 1 h
Yield: 58 %

Procedure:
The ethyl acetate solution of 6,6-dibromopenicillanic acid 1,1-dioxide from Example 1 was combined with 705 ml of saturated sodium bicarbonate solution and 8.88 g of 5% palladium-on-carbon catalyst. The mixture was shaken under an atmosphere of hydrogen, at a pressure of about 5 kg/cm2 for about 1 hour. The catalyst was removed by filtration, and the pH of the aqueous phase of the filtrate was adjusted to 1.2 with 6N hydrochloric acid. The aqueous phase was saturated with sodium chloride. The layers were separated and the aqueous phase was extracted with further ethyl acetate (3×200 ml). The combined ethyl acetate solutions were dried (MgSO4) and evaporated in vacuo to afford 33.5 g (58% yield from 6-aminopenicillanic acid) of penicillanic acid 1,1-dioxide. This product was dissolved in 600 ml of ethyl acetate, the solution was decolorized using activated carbon and the solvent was removed by evaporation in vacuo. The product was washed with hexane. This afforded 31.0 g of pure product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:13]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])=[CH2:14]>CO>[CH2:17]([O:16][P:15]([CH2:13][CH2:14][NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:18]
Reactant: C=CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CO
Product: CCOP(=O)(CCNCCCNC(=O)OC(C)(C)C)OCC
Reaction time: 48 h
Yield: 81.3 %

Procedure:
To a solution of 3-(t-butyloxycarbonylamino) propanamine (77 g, 0.44 mole) in methanol (500 mL) was added diethyl vinylphosphonate 97% (75 g, 0.44 mole; Aldrich 11, 613-0) under nitrogen and kept in a water bath at ~20° C. for 48 hr. The reaction mixture was concentrated in vacua and the residue (~160 g) was put on a pad of "Florisil" (3"×6") and eluted with methylene chloride/hexane 1:1, methylene chloride and finally 10% methanol/methylene chloride to give the title compound as a colorless oil (121 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:44]=[CH:43][C:20]([CH2:21][NH:22][C:23]([C:25]2([CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:31]3[C:26]2=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:24])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23]([C:25]2([CH2:38][CH2:39][CH2:40][CH2:41][N:12]3[CH2:13][CH2:14][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=4)[CH2:10][CH2:11]3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[C:32]3[C:37]2=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:24])=[CH:43][CH:44]=1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1
Reactant: COc1cccc(N2CCNCC2)n1
Product: COc1ccc(CNC(=O)C2(CCCCN3CCN(c4cccc(OC)n4)CC3)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 2 b from 1-(6-methoxy-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxybenzyl-amide.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]([O:11][C:12]2[C:21]3[C:16](=[C:17]([CH3:24])[C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[N:15]=[C:14]([C:25]3[S:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=3)[CH:13]=2)[CH2:8][CH2:7][N:6]1C(OCC1C=CC=CC=1)=O)=[O:4].O>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]([O:11][C:12]2[C:21]3[C:16](=[C:17]([CH3:24])[C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[N:15]=[C:14]([C:25]3[S:26][CH:27]=[C:28]([C:30]([F:31])([F:33])[F:32])[N:29]=3)[CH:13]=2)[CH2:8][CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)C1CC(Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CCN1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)C1CC(Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CCN1
Temperature: 60 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
A mixture of compound 13 (1.08 g) in trifluoroacetic acid (17 mL) was stirred at 60° C. for 5 hrs. The solution was then cooled down at 0° C., water was added, and the mixture was extracted with EtOAc. Organics were washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (DCM/MeOH) to yield compound 14 as a white powder in 97% yield. MS (ESI, EI+) m/z=482 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:17]([O-])=O)[C:6]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)=[N:7][CH:8]=1)#[N:2]>CO.O1CCOCC1.[Pd]>[NH2:17][C:5]1[C:6]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)=[N:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: N#Cc1cnc(N[C@H]2CC[C@H](O)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1cnc(N[C@H]2CC[C@H](O)CC2)c(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-cyano-2-(trans-4-hydroxycyclohexylamino)-3-nitropyridine (3.35 g) in methanol (17 mL) and dioxane (17 mL) was added 10% palladium on activated carbon (383 mg) under nitrogen atmosphere. The mixture was shaken at room temperature under hydrogen atmosphere (3 atm) for 3 hours. The reaction mixture was filtered through a celite pad. The filtrate was concentrated in vacuo to give 3-amino-5-cyano-2-(trans-4-hydroxycyclohexylamino)pyridine (3.15 g) as a brown amorphous.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][C@@H:15]3[C@@H:17]([NH:20]C(=O)OC(C)(C)C)[CH2:18][CH2:19][C@@H:14]3[CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.Cl>C(O)C>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][C@@H:15]3[C@@H:17]([NH2:20])[CH2:18][CH2:19][C@@H:14]3[CH2:13]2)(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21
Agent: Cl
Solvent: CCO
Product: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl(3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate (0.814 g, 1.874 mmol) from Step C and HCl (26.2 mL, 52.5 mmol, 2 M in ether) in ethanol (3 mL) were combined. The reaction was stirred at room temperature overnight and then the volatiles were removed. The compound was purified using a 24 g silica gel cartridge with a gradient of 1-10% methanol (2 N ammonia)/dichloromethane over 20 minutes to give (3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.37 (s, 1H), 8.21 (d, J=7.9, 1H), 7.93 (d, J=7.9, 1H), 7.75 (t, J=7.9, 1H), 3.41 (dd, J=9.8, 2.8, 1H), 3.13 (dd, J=9.7, 3.1, 1H), 3.03-2.98 (m, 1H), 2.97-2.89 (m, 2H), 2.56-2.45 (m, 1H), 2.14 (tdd, J=8.7, 5.9, 2.9, 1H), 1.5-2.0 (m, 2H) 1.95-1.85 (m, 1H), 1.79-1.69 (m, 1H), 1.32-1.15 (m, 2H); MS (ESI+) m/z 335 (M+H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Li]C(CC)C.CN(C)[CH:17]=[O:18].Cl>O1CCCC1.C(OC)(C)(C)C>[F:1][C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: COc1ccccc1F
Agent: Cl
Agent: [Li]C(C)CC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COc1cccc(C=O)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
27 ml (240.62 mmol) of 2-fluoroanisole is dissolved in 700 ml of tetrahydrofuran. At −70° C., 200 ml of sec-BuLi (1.3 M solution in cyclohexane) is added in drops. It is stirred for one hour at −70° C., and then 152 ml of N,N-dimethylformamide, dissolved in 50 ml of tetrahydrofuran, is added in drops at this temperature. After another hour of stirring at −70° C., 380 ml of hydrochloric acid (w=10%) is added in drops. In this case, the batch slowly comes to room temperature. After stirring overnight at room temperature, methyl tert-butyl ether is added, and the organic phase is separated after vigorous stirring. The aqueous phase is extracted two more times with methyl tert-butyl ether. The combined organic extracts are washed with brine and dried. After the desiccant is filtered off, the solvent is spun off, and the residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 25.66 g (69.2%) of the desired compound is isolated.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:11])(=[O:10])[CH:7]([CH3:9])[OH:8].O.[C:13](O)(=[O:15])[CH3:14]>>[C:13]([O:8][CH:7]([CH3:9])[C:6]([OH:11])=[O:10])(=[O:15])[CH3:14]
Reactant: CC(O)C(=O)O
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)OC(C)C(=O)O
Temperature: 114 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
In a distillation reactor at atmospheric pressure, an acid solution formed by combining 30 ml of glacial acetic acid with 0.5 ml concentrated sulfuric acid was maintained at approximately 114° C. A reactant solution was prepared by combining 5.0 ml of an 85% lactic acid solution, by weight (15% water) with 20 ml of glacial acetic acid, and was added dropwise to the distillation reactor. The resulting distillate was collected and analyzed by NMR. After 1 hour, the 2-acetoxy propionic acid product yield was greater than about 90%. A small amount of dimer or polymer was also detected.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:12](O)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(N(CC)CC)C.S(O)(O)(=O)=O.[OH:44][CH2:45][C@@H:46]([C@@H:48]([C@@H:50]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[OH:51])[OH:49])[NH2:47]>C(OCC)(=O)C>[C:12]([NH:47][C@H:46]([C@@H:48]([C@@H:50]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[OH:51])[OH:49])[CH2:45][OH:44])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a mixture of p-toluenesulfonyl chloride (54.43 g; 286 mmoles) and ethyl acetate (425 ml) stirred at 40° C. a solution of oleic acid (86.1 g; purity 90%; 305 mmoles) and triethyl amine (100 ml) in ethyl acetate (160 ml) was added during 30 minutes. After stirring was continued at 43° C. for another 30 minutes this reaction mixture, containing the mixed anhydride of oleic acid, was added to a stirred mixture of phytosphingosine sulphate (84.03 g), triethyl amine (40 ml) and ethyl acetate (275 ml) during 30 minutes at 43° C. The flask that contained the mixed anhydride was rinsed with 50 ml ethyl acetate. After stirring for about 1 hour at 43° C. 400 ml of water was added to the reaction mixture and the pH was adjusted at 6.8 with 18 ml of a HCl solution (37%). The the layers were separated and the organic layer was washed again with 400 ml of water of which the pH was adjusted to 6.4 with 2 ml of a HCl solution (37%). After washing the ethyl acetate layer with 150 ml of a NaCl solution (10% in water) 500 ml of ethyl acetate was removed by distillation. More ethyl acetate (500 ml) was added and another 200 ml of ethyl acetate was removed by distillation. After cooling the ethyl acetate solution to 20° C. the crystalline product was filtered off, washed with ethyl acetate (2×200 ml) and dried in vacuo giving 87.99 g of N-oleoyl-phytosphingosine.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([CH3:27])=[C:22]([CH:24]5[CH2:26][CH2:25]5)[N:23]=4)[CH:20]=3)[C:11](=[O:28])[CH:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:32]>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]([CH3:32])[C:9]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([CH3:27])=[C:22]([CH:24]5[CH2:26][CH2:25]5)[N:23]=4)[CH:20]=3)[C:11](=[O:28])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(NCc4ccc(Cl)s4)cc3=O)cn12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(N(C)Cc4ccc(Cl)s4)cc3=O)cn12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 4-(((5-chloro-2-thienyl)methyl)amino)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (11.5 mg) in DMF (1 ml) was added NaH (60% in oil, 1.7 mg) at 0° C. After the reaction mixture was stirred at 0° C. for 10 min, iodomethane (2.61 μl) was added to the reaction mixture. The mixture was stirred at room temperature for 3 h. The mixture was quenched with water, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was triturated with IPE, and the resulting solid was collected by filtration and washed with EtOAc-IPE to give the title compound (4.0 mg) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][C:17](=O)[CH3:18])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([CH3:18])[N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:28])[CH3:12]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cn2)c1-c1ccccc1

Procedure:
5-Nitro-2-aminopyridine (5 mmol, 0.7 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting solid was triturated with chloroform, and the insoluble material filtered from the reaction mixture. The filtrate was purified over silica gel and yielded the named product (m.p. 146.6° C.-148.6° C.).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH3:5].[CH:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:15]([N:1]([C@@H:2]([CH2:3][CH2:4][CH3:5])[C:6]([O:8][CH2:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1)=[O:7])[CH2:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1)[C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1
Reactant: CCC[C@H](N)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 9 h
Yield: 70.6 %

Procedure:
To a solution of L-norvaline (685 mg, 5.85 mmol) in MeCN (15 mL), BnBr (3.48 mL, 29.24 mmol) and K2CO3 (4.04 g, 29.24 mmol) were added. The mixture was stirred at 60° C. for 9 h, and then cooled down to room temperature and filtered, washing the solid with EtOAc. The filtrates were concentrated in vacuo and the residue purified by column chromatography on silica (100% hexane to hexane/EtOAc 5:1) to obtain benzyl ester 9 as a colorless oil (1.6 g, 71% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19](=[O:20])[CH2:18][CH:17]([C:21]([OH:23])=[O:22])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.Cl[CH2:30]Cl>CO>[CH3:30][O:22][C:21]([CH:17]1[CH2:18][C:19](=[O:20])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)[CH2:16]1)=[O:23]
Reactant: ClCCl
Reactant: O=C(O)C1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Yield: 93 %

Procedure:
7.46 g (24 mmol) (RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid is dissolved in a mixture of 40 ml dichloromethane and 7.5 ml methanol. 0.13 ml concentrated sulfuric acid is added and the reaction mixture hold under reflux over night. The solvent is evaporated and the residue triturated with diethyl ether to yield 7.26 g (93%) of a colorless solid (used in the next step without further purification).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:7]2[CH:8]=[C:9]3[NH:1][CH:2]=[N:3][C:4]3=[N:5][CH:6]=2)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: O=C(O)c1cnc2nc[nH]c2c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1cnc2nc[nH]c2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 71 %

Procedure:
The title compound is prepared from 1H-imidazo[4,5-b]pyridine-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 71% of theory; LC (method 4): tR=1.79 min; Mass spectrum (ESI+): m/z=319 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([N:12]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:25]I.O>O1CCCC1>[CH3:25][N:17]([CH:14]1[CH2:15][CH2:16][N:12]([S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:10])=[O:11])[CH2:13]1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2ccccc2)C1
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil) (49 mg) in tetrahydrofuran (10 ml) was added the product from part (a) (400 mg) as a solution in tetrahydrofuran (5 ml). After 30 minutes methyl iodide (90 ul) was added and the reaction stirred overnight. The mixture was poured into water and the organics extracted into ether. The ether extractions were combined, washed with brine, dried (MgSO4) and concentrated in vacuo to give crude product. Purification by column chromatography (eluent 20% EtOAc/Hexane) gave the subtitle compound as an oil (235 mg).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH3:19])[C:14](OC)=[O:15])=[CH:9][CH:8]=1.[Na+].[Cl-].[NH3:22]>>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH3:19])[C:14]([NH2:22])=[O:15])=[CH:9][CH:8]=1
Reactant: N
Reactant: CCC(C(=O)OC)c1ccc(N)cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: CCC(C(N)=O)c1ccc(N)cc1
Temperature: 17.5 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
The methyl 4-aminophenylbutyrate hydrogensulfate, FW=291.11, 10.0 grams, 34.35 mmol, 1 eq) was dissolved in 20 ml of solution of 20% w/w aqueous NaCl (16 ml H2O and 4 grams of NaCl). To this solution aqueous ammonia (10 eq, 350 mmol, 14.8 molar solution, 24 ml) containing dissolved NaCl (4 grams) was added maintaining temperature 15-20° C. The mixture was stirred for 16 hours at RT. After that the mixture was cooled to 0-5° C. and held at this temperature for at least one hour. The resultant crystalline product was isolated by filtration. Washed with cold water (2 times for 10 ml) and dried under vacuum at 50° C. giving 5.5 g (90% yield) of 4-aminophenylbutyramide. C10H14N2O (MW 178.11); 1H NMR (500 MHz, DMSO-d6) δ: 7.23 ppm (br. s, 1H); 6.83 ppm (d, 2H, J=8.30 Hz); 6.68 ppm (br. s, 1H); 6.49 ppm (d, 2H, J=8.35 Hz); 4.80 ppm (br. s, 2H); 2.38 ppm (t, 2H, J=7.60 Hz); 2.03 ppm (t, 2H, J=7.53 Hz); 1.69 ppm (pentet, 2H, J=7.57 Hz).