Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([CH3:21])([OH:20])[C:17]([O-:19])=O)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].[C:36]1([NH:42][NH2:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O)(=O)C.[N-]1C=CN=C1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4([CH3:21])[O:20][C:24](=[O:25])[N:43]([NH:42][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:17]4=[O:19])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CC(O)(C(=O)[O-])c1ccc(Oc2nc3ccc(Cl)cc3s2)cc1
Reactant: NNc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(c2ccc(Oc3nc4ccc(Cl)cc4s3)cc2)OC(=O)N(Nc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 2-(4-(6-chloro-2-benzothiazolyloxy)phenyl)lactate (1.56 g, 4.1 mmol(in CH2Cl2 (20 mL) was added 1,1'-carbonyldiimidazole (0.86 g, 5.3 mmol) and the resulting mixture was heated at reflux overnight. The solution was diluted with CH2Cl2 (20 mL) and then washed with H2O (two-times with 20 mL) and brine (20 mL). The organic phase was dried (MgSO4) and concentrated under vacuum. The residue was dissolved in CH2Cl2 (20 mL) and PhNHNH2 (0.77 g, 7.8 mmol) and acetic acid (0.45 mL, 7.8 mmol) were added and the resulting mixture was stirred at room temperature until thin layer chromatography indicated no imidazolide remained, approximately 36 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with 1N aqueous HCl (10 mL) and H2O (10 mL). The organic phase was dried (MgSO4) and concentrated under vacuum to yield a red solid, 1.92 g, which was subjected to purification by column chromatography (140 g SiO2 eluting with 3:2:5 diethyl ether/CH2Cl2 /hexanes increasing to a ratio of 4:3:3 diethyl ether/CH2Cl2 /hexanes thereby affording the product of Step B as a light yellow powder, 0.37 g; (19%); m.p. 207°-209° C.; IR (mineral oil): 1820, 1755, 1594, 1245 cm-1 ; 1H NMR (CDCl3); δ7.7 (m,3H), 7.65 (d,1H), 7.5 (d,2H), 7.4 (d,1H), 7.3 (m,2H), 7.0 (t,1H), 6.8 (d,2H), 6.1 (s,1H), 2.0 (s,3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH2:13]([SH:16])[CH2:14][SH:15].B(F)(F)F.CCOCC>CC(O)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[S:16][CH2:13][CH2:14][S:15]1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: SCCS
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1ccc2c(c1)C1(SCCS1)C(=O)N2
Temperature: 60 °C
Reaction time: 0.42 h

Procedure:
5-methyl-1H-indole-2,3-dione (6 g, 37 mmol) was suspended in 100 ml of AcOH. The heterogenous mixture was heated at 60° C. After complete solubilisation, 1,2-ethanedithiol (3.15 ml, 37 mmol) was added and then neat BF3.OEt2 (9.5 ml, 75 mmol) was added dropwise. The reaction was stirred for 25 minutes, in which time the reaction mixture became homogenous. After 20 minutes at room temperature, the reaction was quenched by addition of water, the solid washed several times with large amounts of water and air dried affording 5′-methylspiro[1,3-dithiolane-2,3′-indol]-2′(1′H)-one 6 as a brown solid.
Reaction SMILES: C(OC(=O)C[C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C:9](=O)[NH:8][CH2:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:25](OCC)(=[O:27])[CH3:26].CCCCCC.ClCCl>O1CCCC1>[C:12]1([CH:6]2[CH2:10][CH2:9][NH:8][CH:7]2[CH2:26][CH2:25][OH:27])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC1(c2ccccc2)CNC(=O)C1
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCCCCC
Product: OCCC1NCCC1c1ccccc1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
Combine (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid ethyl ester (301 g, 1.25 mol) and tetrahydrofuran (3.5 L). Cool to about 5° C. Slowly, add portionwise over about 45 minutes a solution of lithium aluminum hydride in tetrahydrofuran (3.9 L, 1 M, 3.9 mol). After the addition is complete heat to 60° C. After 18 hours, cool in an ice-bath. Add water/tetrahydrofuran 1/1 (1.95 L) dropwise at such a rate that the temperature of the reaction mixture does not rise above 20° C. Dilute the reaction mixture with tetrahydrofuran (2.25 L) and stir. After 1.5 hours, filter the reaction mixture. Suspend the solids in diethyl ether (3 L) and filter. Combine the filtrates and concentrate the in vacuo to give a residue. Combine the residue and dichloromethane (4 L) and extract three times with water (1 L). Dry the organic layer over MgSO4, filter, and concentrate in vacuo to obtain a solid. Triturate the solid with diethyl ether (0.3 L), collect by filtration, rinse with diethyl ether, and dry to give the title compound: Rf=0.12 (silica gel dichloromethane/methanol/concentrated aqueous ammonia, 9/1/0.1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH:14]1(B2OC(C)(C)C(C)(C)O2)[CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>O1CCOCC1.O>[Cl:13][C:5]1[CH:4]=[CH:3][C:2]([CH:14]2[CH2:16][CH2:15]2)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(Br)ccc1Cl
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C2CC2)ccc1Cl
Yield: 88 %

Procedure:
In a schlenck tube, a mixture of ethyl 5-bromo-2-chlorobenzoate (7.60 mmol, 2 g), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.59 mmol, 1.3 g), Cs2CO3 (18.97 mmol, 6.18 g), PdCl2dppf.CH2Cl2 (0.76 mmol, 0.620 g) in dioxane (70 ml) and water (15 ml) was heated for 2 hours at 110° C., under argon atmosphere. The solvent was evaporated and the mixture was extracted between ethyl acetate and water. The crude mixture was purified by chromatography over SiO2 eluting hexane/ethyl acetate mixtures and affording 1.5 g (yield 92%) of the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([S:10][CH3:11])[C:5]([C:12]#[N:13])=[C:4]([SH:14])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[S:25][CH:26]=1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([S:10][CH3:11])[C:5]([C:12]#[N:13])=[C:4]([S:14][CH2:21][C:22]2[N:23]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[S:25][CH:26]=2)[N:3]=1
Reactant: CSc1c(C#N)c(N)nc(S)c1C#N
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1c(C#N)c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
7.30 g (32.84 mmol) of the compound from Example 43A (2-amino-6-mercapto-4-(methylthio)pyridine-3,5-dicarbonitrile), 11.03 g (131.36 mmol) of sodium bicarbonate and 9.62 g (39.41 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole were combined in 150 ml of absolute DMF and stirred at room temperature for 12 h. A solid precipitated out; this solid was filtered off with suction through a glass frit and washed three times with water and twice with diethyl ether. The residue was dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][CH2:38]O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:38][CH2:37][C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=5)=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: OCCc1ccccn1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)OCCc5ccccn5)cc4CCC3C2C2CCCC2)cc1Cl

Procedure:
The title compound was prepared according to Method E from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and 2-(2-pyridyl)ethanol. Yellow solid, 194 mg. ES-MS m/z 525 (M+H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Br[CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].CN(P(N(C)C)(N(C)C)=O)C>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C@H:13]([C:14]([OH:16])=[O:15])[CH:17]([CH3:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)C(Br)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Reaction time: 1.5 h

Procedure:
A mixture of 5 g of p-trifluoromethylaniline, 2.25 g of α-bromoisovaleric acid and 2.0 g of potassium carbonate is heated at 100° for 1 hour. After 1.5 hour, 5 ml of HMPT is added and the mixture heated at 100° for 15 hr. The mixture is then poured into water and potassium carbonate added to about pH 11. The mixture is washed with ether, methylene chloride and the aqueous phase acidified to about pH 3 and washed with ether and concentrated. The residue is recrystallized from hexane/ether to yield N-(4-trifluoromethylphenyl)valine, which is reacted with m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(4-trifluoromethylphenyl)valine. MS m/e 443 (M+, 5.9).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:12])[N:3]=1.C(=O)([O-])O.[Na+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>[Cu]I.CN(C)C=O>[Cl:12][C:4]1[N:3]=[C:2]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Agent: [Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)nc1NCc1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of methyl 2,6-dichloropyridine-3-carboxylate (2.06 g), sodium hydrogen carbonate (1.26 g), 4-methoxybenzylamine (1.50 ml), copper(I) iodide (190 mg) and N,N-dimethylformamide (20 ml) was heated to 80° C., and the mixture was stirred for 1 hr and 30 min. The reaction mixture was concentrated under reduced pressure, the obtained residue was diluted with ethyl acetate (150 ml), and the insoluble solid was removed by filtration. To the filtrate was 28% aqueous ammonia (5 ml), and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained yellow oil residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.58 g).
Reaction SMILES: C(O)(=O)C.Cl.[C:6]([C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)(=[O:10])[CH2:7][CH2:8][CH3:9]>O1CCOCC1.[Rh]>[CH:17]1([C:11]2([C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCCC(=O)C1(c2ccccc2)CCNCC1
Agent: [Rh]
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCCC(=O)C1(C2CCCCC2)CCNCC1
Temperature: 80 °C
Yield: 43.1 %

Procedure:
In a Parr bomb under a hydrogen pressure of 6 bar, 100 mg of rhodium on alumina and 0.2 mL of acetic acid are added to a solution of 100 mg (0.5 mmol) of 4-butyryl-4-phenylpiperidine hydrochloride in 10 mL of dioxane. The reaction medium is heated at 80° C. for 12 hours. The reaction is stopped and then filtered through Celite and washed with dichloromethane. The solvents are evaporated off and the residue is taken up in water, basified with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phases are dried over sodium sulfate. The solvents are evaporated off and the residue is chromatographed on silica gel (eluent: 9/1 dichloromethane/methanol). 51.2 mg of 1-(4-cyclohexylpiperidin-4-yl)-butan-1-one in the form of a white powder are obtained in a yield of 61%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][N:5]2[CH:18]=1.C1C(=O)N([I:26])C(=O)C1.C(OCC)(=O)C>C(#N)C>[I:26][C:18]1[N:5]2[N:6]=[C:7]([CH3:17])[CH:8]=[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: CCCC(CCC)c1cc(C)nn2cc(C)nc12
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCC(CCC)c1cc(C)nn2c(I)c(C)nc12
Yield: 99.8 %

Procedure:
In an oven dried nitrogen purged 25 mL round bottom flask, 0.088 g (0.359 mmol) of 2,6-Dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine, in 5 mL of dry acetonitrile is cooled to 0 C. 0.0.81 g (0.359 mmol) of NIS is added and the bath is allowed to expire. TLC in 1:1 Hexanes:Ethyl Acetate indicates SM is gone. Remove solvents to obtain 0.133 g of the title compound, quantitative yield. MS; 1H NMR (DMSO-d6)=6.985 (s, 1H); 3.262-3.190 (m, 1H); 2.502 (s, 3H); 2.480 (s, 3H); 1.823-1.600 (m, 4H); 1.182-0.985 (m, 4H); 0.804-0.768 (m, 6H) ppm.
Reaction SMILES: IC1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[CH3:26][C:27]1[S:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1.[C:41]([O-])([O-])=O.[Na+].[Na+]>O.O1CCOCC1>[CH3:41][C:30]1[S:31][C:27]([C:26]2[N:3]=[CH:4][N:5]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:6]=2)=[CH:28][CH:29]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)s1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A mixture of 4-iodo-1-trityl-1H-imidazole (7.95 g, 18.2 mmol), 5-methylthiophene-2-boronic acid pinacol ester (4.90 g, 21.9 mmol), Na2CO3 (7.66 g, 73.0 mmol) in H2O (20 mL) and dioxane (100 mL) was degassed (N2 bubbling). Pd(PPh3)4 (500 mg) was added and the mixture was heated to reflux for 4 h. The mixture was allowed to cool to room temperature and concentrated. The mixture was diluted with CH2Cl2 and H2O and the organic phase was separated. The aqueous phase was re-extracted (CH2Cl2) and the combined organics were washed (saturated aqueous NaCl), dried (MgSO4), filtered and concentrated to give a solid residue. The residue was purified by flash chromatography (EtOAc/CH2Cl2/hexanes 4:50:50 then 6:50:50 then 8:50:50) to give 4-(5-methylthiophen-2-yl)-1-trityl-1H-imidazole (6.15 g, 83%) as a colourless solid. 1H NMR (CDCl3, 400 MHz) δ2.46 (d, J=0.9 Hz, 3H), 6.62-6.65 (m, 1H), 6.94 (d, J=1.4 Hz, 1H), 6.99 (d, J=3.5 Hz, 1H), 7.15-7.21 (m, 6H), 7.31-7.37 (m, 9H), 7.41 (d, J=1.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ15.3, 75.5, 116.1, 121.7, 125.5, 128.1, 128.1, 129.8, 135.6, 136.4, 137.8, 138.9, 142.2; HRMS (EI) m/z 406.1496 C27H22N2S [M]+. requires 406.1498.
Reaction SMILES: [N:1]12[CH2:11]CCN=[C:7]1[CH2:6]CCC[CH2:2]2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N=C=[O:39])(C)C>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:2]([N:1]([CH3:11])[CH2:7][CH3:6])=[O:39])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CC(C)N=C=O
Reactant: C1CCC2=NCCCN2CC1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Product: CCN(C)C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 36.3 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, isopropyl isocyanate (0.24 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 97.5:2.5) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}[(methylethylamino)]carboxamide (0.25 g, 36%) as a white solid: mp 180-182° C.; 1H NMR (DMSO-d6) δ 11.19 (s, 1H), 7.87-7.68 (m, 3H), 6.33 (t, J=5.9 Hz, 1H), 6.02 (d, J=7.5 Hz, 1H), 5.18-5.11 (dd, J=5.2 and 12.4 Hz, 1H), 4.62 (d, J=5.9 Hz, 2H), 3.73-3.35 (m, 1H), 2.98-2.83 (m, 1H), 2.63-2.50 (m, 2H), 2.08-2.04 (m, 1H), 1.04 (d, J=6.5 Hz, 6H); 13C NMR (DMSO-d6) δ 172.78, 169.85, 167.59, 167.05, 157.36, 141.16, 134.65, 133.39, 131.52, 126.98, 121.64, 48.82, 41.03, 38.64, 30.94, 23.18, 21.99; Anal. Calcd. For C18H20N4O5: C, 58.06; H, 5.41; N, 15.05. Found: C, 58.20; H. 5.44; N, 14.95.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[N:10]=2)[CH:7]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:19](=[O:21])[CH3:20])=[CH:7][N:6]2[CH:8]=1)(=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc2nc(C(=O)c3ccccc3)cn2c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2nc(C(=O)c3ccccc3)cn2c1

Procedure:
The (6-aminoimidazo[1,2-a]pyridin-2-yl)(phenyl)methanone is dissolved in 7 mL of acetic acid and treated with 0.8 mL of acetic anhydride. The reaction medium is refluxed for 2 hours, cooled, filtered and concentrated to dryness. The residue is taken up in ethyl acetate and saturated sodium hydrogen carbonate solution. The organic phase is washed and concentrated, and the product obtained is chromatographed on a column of silica, eluting with a 95/5 mixture of dichloromethane and methanol. The fractions containing the expected product are combined and concentrated to give 150 mg of N-(2-benzoylimidazo[1,2-a]pyridin-6-yl)acetamide as a mixture with N-(3-benzoylimidazo[1,2-a]pyridin-6-yl)acetamide. The two isomers are separated by preparative LC/MS preparative to give 54 mg of purified N-(2-benzoylimidazo[1,2-a]pyridin-6-yl)acetamide in the form of a beige-colored solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]=[C:34]([CH2:36][OH:37])[O:33][N:32]=2)=[CH:27][CH:26]=1)([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:13][N:12]=1)[CH:8]([CH3:10])[CH3:9].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:1][S:2]([O:37][CH2:36][C:34]1[O:33][N:32]=[C:31]([C:28]2[CH:29]=[CH:30][C:25]([C:7]([CH3:6])([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:13][N:12]=3)[CH:8]([CH3:10])[CH3:9])=[CH:26][CH:27]=2)[N:35]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C(C)(c1ccc(-c2noc(CO)n2)cc1)c1ccc(OCc2ccccn2)cn1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(C)(c1ccc(-c2noc(COS(C)(=O)=O)n2)cc1)c1ccc(OCc2ccccn2)cn1
Reaction time: 1.5 h

Procedure:
Methanesulfonyl chloride (27.0 μL, 0.348 mmol) was added to a stirred solution of 3d (100 mg, 0.232 mmol) and DIPEA (101 μL, 0.580 mmol) in DCM (2.00 mL) at 0° C. After approximately 1.5 h, the reaction mixture was poured into water and extracted three times with EtOAc. The combined organic extracts were washed with water, brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound 3e, which was used without further purification in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[C:9](=[O:11])[CH3:10].[Br:13]Br.C(O)(=O)C.C(Cl)(Cl)Cl>>[Br:13][CH2:10][C:9](=[O:11])[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:12]
Reactant: BrBr
Reactant: CC(=O)C(=O)c1ccccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(CBr)C(=O)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A mixture of 1-(2-chlorophenyl)propane-1,2-dione (4.2379 g, 23.208 mmol), bromine (1.1891 mL, 23.208 mmol), and glacial acetic acid (0.67005 mL, 11.604 mmol) in chloroform (58.020 mL, 23.208 mmol) was heated at 60° C. After 17 h of stirring at 60° C., the mixture was removed from heat and concentrated under reduced pressure to give 3-bromo-1-(2-chlorophenyl)propane-1,2-dione as an orange liquid: LC-MS: a peak of m/z 261.0 [M+H(79Br)]+ and 262.9 [M+H (81Br)-]+. The orange liquid was carried on crude without purification for the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([NH:14][C:15]([O:17]CC1C=CC=CC=1)=O)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25]O>[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([NH:14][C:15](=[O:17])[CH3:25])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CO
Agent: [Pd]
Product: CC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C

Procedure:
To a solution of N-(t-butoxycarbonyl)-2(S)-benzyloxycarbonylamino-β-alanine (6.15 g) in methanol (120 ml) was added 10% Pd—C (50% wet, 1.2 g). The mixture was stirred vigorously, and hydrogen gas was bubbled for 1 hour. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The residue was dissolved in tetrahydrofuran (70 ml) and cooled to 0° C. with ice bath. 1N NaOH (36 ml) was added, then acetic anhydride (3.77 ml) was added dropwise under stirring. The mixture was stirred for additional 1 hour at 0° C., then the pH of the mixture was adjusted to 2.5 with aqueous 20% KHSO4. The resultant mixture was extracted with ethyl acetate-tetrahydrofuran (200 ml-100 ml) twice times. The combined organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was recrystallized from diethyl ether to give N-(t-butoxycarbonyl)-2(S)-acetylamino-β-alanine (3.17 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:20])=[C:15]([CH:19]=2)[C:16]([OH:18])=O)=[N:4][NH:5][C:6](=[O:9])[C:7]=1[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:52]([O:54][CH:55]([O:63][CH2:64][CH3:65])[CH2:56][NH:57][CH2:58][C:59]([O:61][CH3:62])=[O:60])[CH3:53]>CN(C=O)C.CCOC(C)=O>[CH2:64]([O:63][CH:55]([O:54][CH2:52][CH3:53])[CH2:56][N:57]([C:16](=[O:18])[C:15]1[CH:19]=[C:11]([CH2:10][C:3]2[C:2]([CH3:1])=[C:7]([CH3:8])[C:6](=[O:9])[NH:5][N:4]=2)[CH:12]=[CH:13][C:14]=1[F:20])[CH2:58][C:59]([O:61][CH3:62])=[O:60])[CH3:65]
Reactant: CCOC(CNCC(=O)OC)OCC
Reactant: Cc1c(Cc2ccc(F)c(C(=O)O)c2)n[nH]c(=O)c1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(CN(CC(=O)OC)C(=O)c1cc(Cc2n[nH]c(=O)c(C)c2C)ccc1F)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-2-fluorobenzoic acid (Preparative Example 2) (1 eq), TBTU (1.2 eq), and DIPEA (1.5 eq) in DMF (0.18M) was added methyl N-(2,2-diethoxyethyl)glycinate (1 eq) (prepared as described in Synthesis 2002, 2, 242-252), and the mixture was stirred at RT for 2 h. The reaction was diluted with EtOAc, washed sequentially with 1N HCl, sat. aq. NaHCO3 solution, and then with brine. The organic layers were dried (Na2SO4), filtered and concentrated and concentrated under reduced pressure. MS (ES) C23H30FN3O6 required: 463, found: 464 (M+H)+; 486 (M+Na)+.