Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].I[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[O:13][CH3:14].C1(OC)C=CC=CC=1.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1.[Cl-].[NH4+]>C(OCC)C>[OH:30][CH:23]([C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[O:13][CH3:14])[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1cccnc1
Reactant: COc1ccc(C(C)(C)C)cc1I
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: COc1ccccc1
Solvent: CCOCC
Product: COc1ccc(C(C)(C)C)cc1C(O)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
270 mg of magnesium was suspended in 2 ml of anhydrous diethyl ether and 0.5 ml of a solution of 2-iodo-4-tert-butylanisole (prepared by dissolving 2.90 g of the anisole in 5 ml of diethyl ether), followed by warming the mixture to initiate the reaction. Upon addition of the remaining ethereal solution of the anisole, the mixture began to reflux. The mixture was refluxed for 30 minutes and then cooled to 0° C., and 1.03 ml of nicotinaldehyde dissolved in 5 ml of diethyl ether was added dropwise to the mixture. After stirring for one hour at 0° C., a saturated aqueous solution of ammonium chloride was added to the mixture which was then extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and an aqueous sodium chloride solution, dried and concentrated. The residue was chromatographed on silica gel column using a mixed solvent of methylene chloride and ethyl acetate (1:1 by volume) as an eluting agent to give 1.76 g of the title compound having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]42[NH:19][C:18](=S)[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:22]>>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]42[N:19]=[C:18]([NH2:22])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCOCC1
Reactant: N
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCOCC1
Temperature: 120 °C
Yield: 74.3 %

Procedure:
6′-Bromo-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4(3H)-thione (Example 25 Step 3, 415 mg, 1.14 mmol) was taken up in NH3 (7M in MeOH, 13 mL, 91 mmol) and the resulting mixture was heated in a microwave reactor at 120° C. for 2×1 h. The mixture was concentrated and the resulting residue was taken up in NH3 (7M in MeOH, 13 mL, 91 mmol) and then heated again for 1 h at 120° C. The mixture was concentrated and the resulting residue was taken up in DCM (10 mL) and sat. aq. NaHCO3 (5 mL) and poured into a phase separator. The organic layer was collected, concentrated and purified on a silica gel column eluted with 0-10% (0.1M NH3 in MeOH) in DCM to give 295 mg (75% yield) of the title compound: 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.36 (dd, 1 H), 7.27 (d, 1 H), 6.68 (d, 1 H), 6.65 (br. s, 1 H), 3.65 (m, 2 H), 3.46 (m, 1 H), 3.38 (m, 1 H), 3.15 (m, 1 H), 3.00 (m, 1 H), 2.18 (s, 3 H), 1.66 (td, 1 H), 1.19 (m, 3 H); MS (ES+) m/z 348[M+H]+.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1OS(C(F)(F)F)(=O)=O)=[O:2].[F-].[Cs+].[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1B(O)O.C>C(#N)C.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>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[C:3]=1[CH:1]=[O:2]
Reactant: COc1ccc2c(C=O)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: COc1ccc2c(C=O)c(-c3ccc(F)cc3F)ccc2c1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
Combine trifluoromethanesulfonic acid 1-formyl-6-methoxy-naphthalen-2-yl ester (2.53 g, 7.6 mmol) with dichlorobis(triphenylphosphine)palladium (II) (0.53 g, 0.8 mmol), cesium fluoride (5.75 g, 37.8 mmol), and 2,4-difluorophenylboronic acid (2.39 g, 15.1 mmol) in acetonitrile (25 mL). Heat to reflux for 1 hour. Cool to room temperature, add DARCO, and filter. Concentrate in vacuo, dilute with dichloromethane and wash with saturated aqueous sodium carbonate. Dry the organic layer over magnesium sulfate, filter, add silica gel, and concentrate in vacuo. Purify the residue by column chromatography using an eluent of 1.5:1 hexanes:dichloromethane to give 1.4 g of the title compound (62%).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[C:37]([O:44][CH3:45])[CH:36]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[CH2:42]([O:41][C:38]1[CH:39]=[CH:40][C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)=[CH:36][C:37]=1[O:44][CH3:45])[CH3:43]
Reactant: NNc1ncccn1
Reactant: CCOc1ccc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc1OC
Temperature: 85 °C
Reaction time: 20 h
Yield: 32.8 %

Procedure:
After adding 102 mg of 2-hydrazinopyrimidine and 129 μl of triethylamine to a solution of 435 mg of {2-(4-ethoxy-3-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 15 ml of DMF, the mixture was stirred at 85° C. for 20 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 20 ml of a methanol:THF=1:1 mixed solvent. Next, 186 μl of acetic acid and 292 mg of sodium cyanotrihydroborate were added to the solution and the mixture was stirred at room temperature for 2 hours and 30 minutes. After adding ethyl acetate to the reaction mixture, it was filtered through a small amount of NAM silica gel, and the silica gel was washed with ethyl acetate-methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (152 mg).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=2[CH:16]=1.C(Cl)Cl.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=2[CH:16]=1
Reactant: CCOC(=O)c1cc2cc(OC)ccc2s1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(O)ccc2s1
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 5-methoxy-1-benzothiophene-2-carboxylate (1.77 g, 7.49 mmol) in methylene chloride (15 mL) was added dropwise 1 M boron tribromide methylene chloride solution (22.5 mL, 22.5 mmol) at −20° C., and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was poured into ice, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was passed through silica gel. The solvent was evaporated under reduced pressure, and the obtained solid was washed with hexane to give the title compound (1.53 g, yield 92%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.C(#N)C.Br[C@H:22]([CH3:37])[C:23]([N:25]1[C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[CH2:27][C@H:26]1[C:34]([OH:36])=[O:35])=[O:24]>ClCCl>[CH2:6]([O:5][C:3]([C@@H:2]([NH:1][C@@H:22]([CH3:37])[C:23]([N:25]1[C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[CH2:27][C@H:26]1[C:34]([OH:36])=[O:35])=[O:24])[CH2:8][CH2:9][CH3:10])=[O:4])[CH3:7]
Reactant: CCC[C@H](N)C(=O)OCC
Reactant: C[C@@H](Br)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)O
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC[C@H](N[C@@H](C)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)O)C(=O)OCC

Procedure:
Introduce into a reactor 105 g of ethyl (2S)-2-aminopentanoate, 135 ml of triethylamine and 135 ml of acetonitrile, and then bring the mixture to 60° C. and slowly add a solution of 200 g of the compound obtained in Step A in 1.3 litres of dichloromethane, and subsequently reflux for 4 hours. After returning to ambient temperature, wash the mixture with water and with a dilute acetic acid solution, and then evaporate off the solvents to yield (2S)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]propionyl}-2,3,4,5,6,7-hexa-hydro-1H-indole-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([OH:11])[CH:5]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])[CH:5]=1
Reactant: OCCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(Cl)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.0 g (10.72 mmol) of 4-Chloro-3-hydroxy-benzoic acid methyl ester was dissolved in 20 ml of anhydrous tetrahydrofuran. To this solution was added 2.25 g (11.79 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 10.71 g (equivalent to 32.2 mmol PPh3) of triphenylphosphine derivatized polystyrene and 5.6 g (32.2 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/6).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[N:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1>CO>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:1]=[CH:15][C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)=[CH:4][CH:5]=1
Reactant: NCc1ccncc1
Reactant: O=Cc1ccncc1
Solvent: CO
Product: C(=NCc1ccncc1)c1ccncc1
Reaction time: 0.01 h

Procedure:
In this Example, reductive amination of 4-pyridine-carboxaldehyde (2) with 4-(aminomethyl)pyridine (1) was carried out using a one-pot two-step protocol to produce bis((pyridin-4-yl)methyl)amine (4). Time-resolved mass spectra of the aldehyde-amine condensation step and the imine reduction step are shown in FIG. 16. Ions were identified according to their m/z values and confirmed by tandem mass experiment. Reactant 1 was first injected into the methanol reaction solvent. Ions of protonated 1 at m/z 109 were detected at 0.4 min later, on the heels of which the protonated dimer at m/z 217 appeared and reached its steady state within 4.8 s. (FIG. 16 panels A-B) After reactant 2 was injected into the reaction solution and the protonated methanol adduct ions of the monomer and dimer of 2 at m/z 140 and 279 showed up. The ions of the intermediate (pyridin-4-yl)-N-((pyridin-4-yl)methylene)methanamine (3) at m/z 198 and 230 formed quickly and the intensity increased sharply (FIG. 16 panel C). The intensity of ions of 1 decreased but the ions did not disappear, which corresponded to the fact that this is an equilibrium reaction (FIG. 16 panel D). About 50 min later, sodium borohydride solution was injected into the system. The sodiated adduct ions of product 4 at m/z 222 started to appear, while the intermediate ions of 3 decreased a lot (FIG. 16 panel E). Ten minutes later, the peak of the product 4 was reaching its highest intensity (FIG. 16 panel F). The selected ion chronogram shows dynamic changing of ions corresponding to the precursor 1, intermediate 3 and product 4 (FIG. 17). The kinetic process of reductive amination can be clearly seen. The first condensation step of this reaction happened very fast; once 2 was added to the solution of 1, it took less than 1 min for the reaction to reach equilibrium. The intermediate 3 was generated simultaneously with the decrease of 1. The second reduction step was not as fast as the first step. With the reduction of intermediate 3, the first step was driven to the right. Thus ions of 1 were depleted. Altogether, it took around 10 min for the product 4 to reach its highest intensity. The total monitoring time was 90 min without any clogging in the fused-silica capillary using high concentrations of reaction solution that are representative of those of industrial interest.
Reaction SMILES: N#N.[C:3]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[NH:4][NH2:5].Br[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O.C1(C)C=CC=CC=1>[Cl:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([NH:5][NH:4][C:3]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH:18]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: Clc1ccnc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NNc1cc(Cl)ccn1
Temperature: 100 °C
Yield: 34.9 %

Procedure:
4-Chloro-2-hydrazinylpyridine, 2HCl: In microwave vial was added toluene (4 mL) and purged with N2 for 5 min. tert-Butyl carbazate (66.6 mg, 0.494 mmol), 2-bromo-4-chloropyridine (95 mg, 0.494 mmol), Cs2CO3 (161 mg, 0.494 mmol), and PdCl2(dppf)-CH2Cl2 adduct (4.03 mg, 4.94 μmol) were added. The sealed tube was heated at 100° C. for 5 h. To the reaction mixture was added water, brine and the mixture was extracted with EtOAc (2×). The combined organic layer was concentrated and purified by silica gel chromatography to provide tert-butyl 2-(4-chloropyridin-2-yl)hydrazinecarboxylate (42 mg, 35%) as red oil. MS(ESI) m/z: 244.2 (M+H)+. To the above oil was added 4 N HCl in dioxane (2 mL) and the reaction was stirred at rt for 2 h. The mixture was concentrated to dryness to give the desired (36 mg, 34%) as a white solid. MS(ESI) m/z: 144.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1(N)[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][CH2:6]1)(=[O:4])=[O:3].Cl.N([O-])=O.[Na+].[I-:19].[K+]>O>[I:19][C:7]1[CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=1
Reactant: COC1=CC(N)(S(C)(=O)=O)CC=C1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(I)cc(S(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of 1-methanesulfonyl-5-methoxy-phenylamine (1.0 g, 4.94 mmol) in water (2.66 mL) was added a concentrated hydrochloric acid (2.21 mL, 29.66 mmol, 36%) at 0° C. To this mixture was added a chilled solution of sodium nitrite (0.622 g, 8.89 mmol) in water (3.78 mL) dropwise with a vigorous stirring. Then, the resulting colored mixture was stirred for 15 min at 0° C., and a cold solution of potassium iodide (1.64 g, 9.88 mmol) in water (3.78 mL) was added carefully. During this addition, a black brown solid was formed and after addition the ice bath was removed, and the reaction mixture was stirred for 2 days at room temperature. Then, the reaction mixture was diluted with water (50 mL) and saturated sodium thiosulfate solution (100 mL). The organic compound was extracted into ethyl acetate (3×50 mL). The combined organic extracts were washed with brine solution (100 mL) and dried over anhydrous magnesium sulfate. The filtration of the drying agent and concentration of the filtrate under reduced pressure gave the crude residue which was purified by using a silica gel column, eluting with 0-35% ethyl acetate in hexanes to obtain 3-iodo-1-methanesulfonyl-5-methoxy-benzene (1.08 g, 70%) as a white solid: ES(+)-HRMS m/e calcd for C8H9IO3S (M+H)+ 312.9390, found 312.9390.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26](OC)=[O:27])[CH2:22][CH2:21]3)=[N:9][C:10]=2[C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:6][N:7]=1.[OH-].[Na+].C(O[CH2:36][CH3:37])(=O)C>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:20]3[CH2:21][CH2:22][C@H:23]([C:26]([NH:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:36][CH:37]=4)=[O:27])[CH2:24][CH2:25]3)=[N:9][C:10]=2[C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn32)CC1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: Nc1nccn2c1c(-c1cc3ccccc3[nH]1)nc2[C@H]1CC[C@H](C(=O)Nc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
After 25 min, the resulting solution was treated with methyl trans-4-(8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate (30 mg, 0.08 mol) and the mixture stirred at rt overnight. The mixture was then stirred with 2M NaOH (20 mL) and ethyl acetate (20 mL) for 10 min., then the organic phase was separated and the aqueous extracted EtOAc (3×15 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), then dried over Na2SO4 and concentrated in vacuo to give crude product which was subjected to mass-directed preparative HPLC to afford pure desired product. 1H NMR (d6-DMSO, 400 MHz): δ 11.45 (br s, 1H), 10.12 (s, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.25 (d, J=4.8 Hz, 1H), 8.14 (s, 1H), 8.08 (dd, J=8.0, 1.6 Hz, 1H), 7.71 (d, J=5.2 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.34 (m, 1H), 7.15-7.00 (m, 3H), 6.65 (s, 1H), 6.42 (br s, 2H), 3.22 (m, 1H), 2.47 (m, 1H), 2.15-1.95 (m, 4H), and 1.85-1.65 (m, 4H). MS (ES+): m/z 452.17 [MH+].
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][O:37][C:38]1[C:43]2[N:44]=[C:45]([NH2:47])[S:46][C:42]=2[C:41]([CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][O:49]2)=[CH:40][CH:39]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[CH3:36][O:37][C:38]1[C:43]2[N:44]=[C:45]([NH:47][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][N:11]=[C:3]([CH3:2])[CH:4]=3)[S:46][C:42]=2[C:41]([CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][O:49]2)=[CH:40][CH:39]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: COc1ccc(C2CCCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C2CCCCO2)c2sc(NC(=O)c3ccnc(C)c3)nc12

Procedure:
From 2-methyl-isonicotinic acid hydrochloride, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-2-yl)-benzothiazol-2-ylamine in dioxane and DMF. ES-MS m/e (%): 384 (M+H+, 100).
Reaction SMILES: O1C=CC=C1[C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)/[CH:9]=[C:10]1\[CH2:11][CH2:12][C:13]2[NH:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:17]\1=2.[C:25]([O:28][CH2:29][CH3:30])(=O)[CH3:26]>[Pd]>[O:28]1[CH2:29][CH2:30][CH:26]([C:6]2[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=2)[CH2:9][CH:10]2[C:17]3[CH:16]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[NH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:25]1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cc2c([nH]1)CC/C2=C\c1cccc(-c2ccco2)c1
Agent: [Pd]
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(C2CCOC2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(E)-Methyl 4-(3-(furan-2-yl)benzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.066 g, 0.207 mmol) was dissolved in ethyl acetate (5 mL). Then palladium on carbon (5%) was added and the reaction placed under a hydrogen atmosphere using a balloon, stirred at room temperature for 5 h, then filtered through celite. The filtrate was concentrated and purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-25% EtOAc/heptane affording the title compound. 0.028 g.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=O)[O:3]1.C1COCC1.[CH3:20][NH2:21]>CC(O)=O>[CH3:20][N:21]1[C:4](=[O:3])[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([OH:13])=[O:12])[CH:6]=2)[C:2]1=[O:1]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CN
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1C(=O)c2ccc(C(=O)O)cc2C1=O
Reaction time: 12 h

Procedure:
To a microwave vial was added 1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid (200 mg, 1.041 mmol), THF (2 mL) and methylamine (2.0M THF, 2.0 mL). The flask was irradiated in a microwave at 100° C. for 5 min. At this time, AcOH (glacial, 0.4 mL) and an additional portion of methylamine (2.0M THF, 2.0 mL) were added, and the flask was placed in a the microwave at 100° C. for 2 h. The flask was allowed to cool and then azeotropically dried (toluene, 3×5 mL). The flask was placed under a high vacuum for 12 h to provide 2-methyl-1,3-dioxoisoindoline-5-carboxylic acid which was used directly in the amide coupling reaction without further purification.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14](Cl)=[O:15]>C(Cl)Cl>[Cl:12][C:13]([Cl:18])([Cl:17])[C:14]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:15]
Reactant: C=CCN
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCNC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.4 %

Procedure:
To a stirred solution of allylamine (5 g, 88 mmol) and triethylamine (9.6 g, 95 mmol) in CH2Cl2 (200 mL) at -10° C. was added trichloroacetyl chloride (16.7 g, 92 mmol). The resulting solution was allowed to gradually warm to RT and stir for 24 h. The reaction solution was extracted with brine (satd., 100 mL) and dried (Na2SO4) to yield 17 g (96%) of the title compound as a white solid.
Reaction SMILES: [Li+].[OH-].[C:3]([NH:6][C@@H:7]1[C@H:12]([OH:13])[CH2:11][C:10]([C:14]([O:16]C)=[O:15])=[CH:9][C@H:8]1[O:18][CH:19]([CH3:21])[CH3:20])(=[O:5])[CH3:4]>CO>[C:3]([NH:6][C@@H:7]1[C@H:12]([OH:13])[CH2:11][C:10]([C:14]([OH:16])=[O:15])=[CH:9][C@H:8]1[O:18][CH:19]([CH3:21])[CH3:20])(=[O:5])[CH3:4]
Reactant: COC(=O)C1=C[C@@H](OC(C)C)[C@H](NC(C)=O)[C@H](O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@@H]1[C@H](O)CC(C(=O)O)=C[C@H]1OC(C)C
Reaction time: 10 h
Yield: 93.7 %

Procedure:
Aqueous LiOH solution (0.1N, 15 mL) was added to a room temperature solution of Example 13L (23 mg, 0.085 mmol) in methanol (5 mL). After stirring for 10 hours, the reaction mixture was acidified to pH 5-6 with DOWEX® 50WX2-200 ion-exchange resin, filtered and concentrated. The concentrate was purified by flash chromatography using acetic acid/ethyl acetate (1/5) to afford 20.5 mg (94%) of the desired product as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:15](=[O:16])[O:14][C:12](=[O:13])[C:8]2=[N:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].[CH3:17][C@@:18]([C:23]([NH2:25])=[O:24])([CH:20]([CH3:22])[CH3:21])[NH2:19]>>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[N:9][C:8]([C:12](=[O:13])[NH:19][C:18]([C:23](=[O:24])[NH2:25])([CH3:17])[CH:20]([CH3:22])[CH3:21])=[C:7]([CH:6]=1)[C:15]([OH:14])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(nc1C)C(=O)OC2=O
Reactant: CC(C)[C@](C)(N)C(N)=O
Product: CC(=O)Oc1cc(C(=O)O)c(C(=O)NC(C)(C(N)=O)C(C)C)nc1C

Procedure:
6.3 g (28.48 mmol) 5-acetoxy-6-methyl-pyridine-2,3-dicarboxylic acid anhydride and 4.1 g (31.33 mmol) 2-methylvalinamide are stirred under nitrogen for 2 days at room temperature, and then the precipitated crystalline product is filtered off.