Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[S:6](Cl)(Cl)=[O:7].[CH2:10]([O:17][C:18](=[O:30])[C@@H:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][OH:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.I([O-])(=O)(=O)=[O:32].[Na+]>ClCCl.O.[Ru](=O)=O>[C:26]([O:25][C:23]([N:22]1[C@H:19]([C:18]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:30])[CH2:20][O:21][S:6]1(=[O:7])=[O:32])=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=S(Cl)Cl
Agent: O=[Ru]=O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)OCc2ccccc2)COS1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
In an inert atmosphere and under exclusion of moisture, at 0° C. a solution of 6.9 g (102 mmol) of imidazol in 80 ml of dichloromethane was treated dropwise within 15 minutes with a solution of 2.2 ml (30 mmol) of thionylchloride in 30 ml of dichloromethane. After complete addition, the reaction mixture was left to warm to room temperature and stirring was continued for 30 minutes. Thereafter, a solution of 5.0 g (17 mmol) of (S)-2-tert-butoxycarbonylamino-3-hydroxy-propionic acid benzyl ester in 20 ml of dichloromethane was added dropwise at −78° C. After 1 hour at −78° C., the reaction mixture was left to warm to room temperature and stirring was continued overnight. For the working-up, the reaction mixture was quenched with 150 ml of a solution (10%) of citric acid. The organic layer was separated, washed with water, dried over sodium sulfate, and evaporated. The crude product (5.5 g of a colourless oil) was dissolved in 50 ml of ethyl acetate and cooled to 0° C. Thereafter, an aqueous solution (10%) of 9.0 g (29 mmol) of sodium metaperiodate, cooled to 0° C., and 0.36 g (2 mmol) of ruthenium(IV)oxide hydrate were added. After stirring at 0° C. for 30 minutes, the organic layer was separated, filtered over Dicalit and silica gel, and, finally, evaporated under reduced pressure. There were obtained 4.0 g (66%) of the (S)-2,2-dioxo-2λ6-[1,2,3]oxathiazolidine-3,4-dicarboxylic acid 4-benzyl ester 3-tert-butyl ester as a grey solid, [α]589=−21.51° (c=1.0% in MeOH), MS m/e (%): 356.0 (M−H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11](S)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].S(Cl)([Cl:17])=O.CN(C=O)C>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([Cl:17])=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cccc2nc(S)oc12
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2nc(Cl)oc12
Yield: 80.1 %

Procedure:
To 2-mercapto-benzooxazole-7-carboxylic acid methyl ester (1.0 g, 4.78 mmol, 1.0 equiv) was added thionyl chloride (8.0 g, 4.9 mL, 67.6 mmol, 14.0 equiv) and anhydrous DMF (0.4 g, 0.4 mL, 5.19 mmol, 1.1 equiv) and the reaction mixture heated to reflux for 15 min. The solvent was removed under reduced pressure, the crude oil azeotroped twice with xylene and the crude material purified with column chromatography on silica eluting with ethyl acetate/hexane (1:1) to afford 0.81 g (81%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 4.03 (s, 3H), 7.44 (t, J=7.9 Hz, 1H), 7.87 (dd, J=7.9 Hz, J=1.1 Hz, 1H), 8.01 (dd, J=7.9 Hz, J=1.1 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 52.46, 115.07, 124.36, 124.82, 127.54, 142.39, 150.35, 152.24, 163.88. MS (ISP): 212.0 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)(O)=[O:6]>>[ClH:3].[Cl:3][C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2nccc(-n3cc(C(=O)O)c4ccccc43)c2c1
Product: COc1ccc2nccc(-n3cc(C(=O)Cl)c4ccccc43)c2c1
Product: Cl

Procedure:
4 cm3 of thionyl chloride are added to 0.57 g (1.79 mmol) of 3-carboxy-1-(6-methoxyquinol-4-yl)-1H-indole under an argon atmosphere. After stirring at reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated three times with 30 cm3 of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.67 g of 3-chlorocarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole hydrochloride in the form of a yellow powder which is used directly in the following step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH2:20])=[O:19])(=[O:7])=[O:6].C(N(CC)CC)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>CCOC(C)=O>[Br:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:18]([NH2:20])=[O:19])=[C:8]2[S:5]([NH:4][CH2:3][CH2:2][NH:1][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])(=[O:6])=[O:7]
Reactant: NCCNS(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NCCNS(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12
Temperature: 65 °C
Reaction time: 60 h

Procedure:
A solution of the product from Example 63 (15 mg, 0.038 mmol), triethylamine (0.017 mL, 0.11 mmol) and ethanesulfonyl chloride (0.004 mL, 0.04 mmols) were combined in a sealed tube and heated to 65° C. overnight. The solvent was removed under a stream of N2 and replaced with DMF. After adding an additional 3 equivalents of ethanesulfonyl chloride and triethylamine, the reaction was heated to 65° C. for 8 hours and stirred at room temperature for 60 hours. The mixture was diluted with EtOAc and washed with 10% Na2CO3 and brine, dried over Na2SO4, filtered and concentrated in vac o. Purification by reversed-phase preparative HPLC gave the titled compound. ESI+ MS: 453 [M+H]+.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2](O)=O.[CH3:7][C:8]([NH:11][NH2:12])([CH3:10])[CH3:9].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.[OH-].[Na+].CCCCCC>[CH3:7][C:8]([N:11]([C:1](=[O:6])[C:2]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)[NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:10])[CH3:9]
Reactant: O=C(O)C(=O)O
Reactant: CC(C)(C)NN
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
The 1,1-dimethylethylhydrazine oxalate (2 g) was dissolved in toluene and neutralized with 50% aqueous sodium hydroxide. To this solution was added benzoyl chloride (4.02 g) and sodium hydroxide (50% Aq. solution) (2.45 g) at 25° C. The reaction mixture was warmed to room temperature and stirred 3 hours. The mixture was diluted with hexane and filtered to afford the product as a white solid (0.5 g).
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[C:11]([C:13]1[C:19]([C:20]#[N:21])=[C:18]([OH:22])[CH:17]=[CH:16][C:14]=1[OH:15])#[N:12].[CH3:23][C:24](=O)[CH2:25]C>>[CH2:1]([O:22][C:18]1[CH:17]=[CH:16][C:14]([O:15][CH2:23][CH2:24][CH3:25])=[C:13]([C:11]#[N:12])[C:19]=1[C:20]#[N:21])[CH2:2][CH3:3]
Reactant: CCCI
Reactant: CCC(C)=O
Reactant: N#Cc1c(O)ccc(O)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOc1ccc(OCCC)c(C#N)c1C#N
Temperature: 25 °C

Procedure:
Propyl iodide (15 mL, 0.16 mol) and anhydrous potassium carbonate (24 g, 0.17 mol) are combined with to a solution of 2,3-dicyanohydroquinone (3.0 g, 0.019 mol) in 100 mL of 2-butanone. The reaction mixture is refluxed for 18 hr. under a stream of argon, cooled to room temperature and the solid collected by filtration. The residue is then added to water (100 mL) to dissolve the potassium carbonate and the resulting solid is collected by filtration and dried under vacuum to yield 3.4 g (74%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][C:55]=1[NH:56][C@@H:57]([CH3:61])[CH2:58][O:59][CH3:60])[N:52]([CH3:62])[C:51](=[O:63])[C:50]2([CH3:65])[CH3:64]>CN1C(=O)CCC1>[CH3:60][O:59][CH2:58][C@@H:57]([NH:56][C:55]1[CH:54]=[C:53]2[C:49]([C:50]([CH3:65])([CH3:64])[C:51](=[O:63])[N:52]2[CH3:62])=[CH:48][C:47]=1[NH:46][C:10]([C:4]1[CH:5]=[C:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)=[O:12])[CH3:61]
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Reactant: COC[C@H](C)Nc1cc2c(cc1N)C(C)(C)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC[C@H](C)Nc1cc2c(cc1NC(=O)c1cc(C)c(=O)n(C)c1)C(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D1 (47 mg; 0.28 mmol), is dissolved in NMP (500 μl) and DIPEA (135 μl; 0.85 mmol) and HATU (111 mg; 0.29 mmol) is added. The reaction mixture is stirred at ambient temperature for 15 min. 5-Amino-6-((S)-2-methoxy-1-methyl-ethylamino)-1,3,3-trimethyl-1,3-dihydro-indol-2-one E-1.1 (85 mg; 0.31 mmol) dissolved in NMP (500 μl) is added and stirring is continued for 12 h at ambient temperature. The reaction mixture is poured on water and extracted with DCM once. The organic phase is dried with MgSO4 and concentrated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[H-].[Na+].F[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][CH:14]=1.CO>C1COCC1>[N+:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([O:9][CH2:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH2:1])=[CH:14][CH:15]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Reactant: Nc1cnccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cnccc1COc1ccc([N+](=O)[O-])c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
To a solution of (3-amino-pyridin-4-yl)-methanol (5) (4.00 g, 32.2 mmol) in anhydrous THF (160 mL) at 0° C. was added sodium hydride (1.55 g, 38.7 mmol, 60 wt %). After stirring for 20 min, 1-fluoro-4-nitronaphthalene (6.16 g, 32.2 mmol) was added, the ice bath removed and the reaction mixture left to warm to RT and stir for 12 hr. The reaction mixture was partitioned between EtOAc (200 mL) and saturated aq NaHCO3 solution (150 mL). The remaining yellow solid was collected by filtration and washed sequentially with water (50 mL), MeOH (50 mL) and diethyl ether (100 mL) and was identified as the desired product by LC-MS and 1H NMR. The filtrate was returned to a separating funnel; the organic phase was collected and washed with brine (100 mL), dried and concentrated in vacuo to afford an orange residue. Trituration of the orange residue with MeOH (200 mL) afforded an orange solid which was washed with diethyl ether (200 mL). LC-MS and 1H NMR analysis of the orange solid were identical to that observed for the insoluble solid obtained earlier. The two products were combined to afford 4-((4-nitronaphthalen-1-yloxy)methyl)pyridin-3-amine (6) (7.80 g, 77%): m/z 296 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.CCN(CC)CC.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][N:14]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CNCc2ccc(-c3ccnc(Cl)n3)s2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CN(Cc2ccc(-c3ccnc(Cl)n3)s2)C(=O)c2ccccc2)cc1
Reaction time: 18 h

Procedure:
[5-(2-Chloro-pyrimdin-4-yl)-thiophen-2-ylmethyl]-(4-methoxybenzyl)-amine (22 mg, 0.063 mmol) was dissolved in CH2Cl2 (1 mL) and treated with pyridine (4.3 uL, 0.076 mmol) and Et3N (17.8 uL, 0.127 mmol), followed by benzoyl chloride (8.9 uL, 0.765 mmol). The mixture was allowed to stir for 18 h and was then washed with 1 N HCl, dried over Na2SO4 and concentrated. The material was used crude in the next step.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C(N(CC)CC)C.BrCC(=O)C(C)(C)C>C1COCC1>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[C@H:6]([CH2:7][CH3:8])[CH3:9]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Agent: CC(C)(C)C(=O)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 127.1 %

Procedure:
Using the procedure described in Example 5, treatment of a solution of L-proline-L-isoleucine benzylamide (69 mg, 0.21 mmol), with triethylamine (151 uL, 1.08 mmol, 5.0 eq), and 1-bromopinacolone (58 uL, 0.43 mmol, 2 eq) in THF (5 mL), provided 35 mg (39%) of L-isoleucine, N-[1-(2-tert-butyl-2-oxoethyl)-L-proline] benzylamide as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH2:10][C@@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:12][C@@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH3:10])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](COc1ccc(Br)nc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
To a solution of 6-bromopyridin-3-ol (4.90 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (4.93 g) and triphenylphosphine (11.06 g) in THF (100 mL) was added dropwise a toluene solution (1.9 M, 22 mL) of diisopropyl azodicarboxylate, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added ethyl acetate, and the mixture was washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.35 g).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH3:7][C:8]12[CH:17]=[CH:16][CH2:15][CH2:14][CH:13]1[C:12](=[O:18])[O:11][C:9]2=[O:10]>>[CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH3:7][C:8]1([CH:17]=[CH:16][CH2:15][CH2:14][CH:13]1[C:12]([OH:11])=[O:18])[C:9]([OH:5])=[O:10]
Reactant: CC12C=CCCC1C(=O)OC2=O
Solvent: OCCCCO
Product: CC1(C(=O)O)C=CCCC1C(=O)O
Reaction time: 2 h

Procedure:
A 1-liter separable flask fitted with a stirrer, thermometer and condenser provided with a calcium chloride desiccator was charged with 90.1g (1 mol) of 1,4-butanediol and 332g (2 mols) of methyltetrahydrophthalic anhydride. Reaction was conducted 2 hours at 160° to 180° C, providing 420g of 2:1 adduct of methyltetrahydrophthalic acid 1,4-butanediol having an acid value of 259.3.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:1]1([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[O:13][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CBr
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3-phenylphenol (5.00 g), methyl bromoacetate (3.1 ml) and potassium carbonate (8.1 g) in DMF was stirred at room temperature. After five hours, the reaction mixture was diluted with water (100 ml) and then extracted with ether. The combined organic layers were washed with aqueous sodium carbonate followed by brine and then dried, filtered and evaporated to give crude methyl (3-phenylphenoxy)acetate (7.2g) as a pale yellow liquid, 1H NMR (CDCl3) delta 3.8 (3H,s), 4.7 (2H,s), 6.8-7.6 (9H,m) ppm.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>CCCCCCC.CCOC(C)=O>[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and 6-methoxypyridin-3-ylboronic acid (CAS RN 163105-89-3) and using a gradient of n-heptane:EtOAc (100:0 to 60:40) for the chromatographic separation. Colorless solid (74%). MS (ESI): m/z=456.113 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH3:21])[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[CH3:20][N:18]([CH3:19])[CH2:17][CH2:16][N:15]([CH3:21])[C:10]1[N:9]=[C:8]([C:4]2[S:3][C:2]([NH:1][C:22](=[O:24])[CH3:23])=[N:6][C:5]=2[CH3:7])[CH:13]=[C:12]([CH3:14])[N:11]=1
Reactant: Cc1cc(-c2sc(N)nc2C)nc(N(C)CCN(C)C)n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(C)c(-c2cc(C)nc(N(C)CCN(C)C)n2)s1

Procedure:
N-[4-(2-Amino-4-methyl-thiazol-5-yl)-6-methyl-pyrimidin-2-yl]-N,N′,N′-trimethyl-ethane-1,2-diamine (0.020 g, 0.065 mmol) in acetic anhydride (1 ml) is heated at 60° C. for 2 hours. When cool, the solvent is removed in vacuo and the residue is partitioned between ethyl acetate (30 ml) and water (30 ml). The organic extract is removed, dried (MgSO4) and the solvent removed to give the titled compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[O:25]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[C:6]([C:8]3[N:12]4[CH:13]=[C:14]([NH:17][CH:18]5[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]5)[CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:26]1
Reactant: OC1CCC(Nc2ccc3ncc(-c4ccnc(Cl)c4)n3c2)CC1
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC1CCC(Nc2ccc3ncc(-c4ccnc(-c5ccoc5)c4)n3c2)CC1

Procedure:
To [4-[3-(2-chloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino]-cyclohexanol (Example 2.1) (1 eq, 100 mg, 0.29 mmol), 3-furyl boronic acid (1.05 eq, 0.3 mmol, 34 mg), Na2CO3 (2 eq, 0.58 mmol, 62 mg) in ethanol (2 ml) and H2O (0.7 ml), under inert atmosphere is added tetakis(triphenylphosphine)palladium (0.1 eq, 0.029 mmol, 21 mg). The reaction is heated in using microwave radiation at 80° C. for 2 hours. The mixture is diluted with H2O (5 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with 0-2.5% methanol in EtOAc to afford the title compound; [M+H]+375
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:48]1([C@H:54]([NH2:56])[CH3:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CC(N(C)C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:56][C@@H:54]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH3:55])=[O:6]
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)c1ccc(-c2ccncc2)cc1Cl)c1ccccc1
Yield: 70.74 %

Procedure:
A 20-ml scintillation vial was charged with a solution of 2-chloro-4-(pyridin-4-yl)benzoic acid in DMA (20.0 mg, 0.085 mmol, 1.0 eq), a solution of HATU in DMA (39.06 mg, 0.103 mmol, 1.20 eq), and triethylamine (28.83 μL, 0.205 mmol, 2.40 eq). The mixture was briefly shaken and a solution of (R)-1-phenylethanamine (14.52 mg, 0.1198 mmol, 1.40 eq) in DMA was added. The mixture was left to shake at room temperature over-night. The mixture was then concentrated in vacuo and dissolved in 1.4 ml of DMSO/methanol (1:1 v/v) and submitted for reverse phase purification to afford (R)-2-chloro-N-(1-phenylethyl)-4-(pyridin-4-yl)benzamide (27.30 mg, 70.74% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH:20]=O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:22][C:23]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]([N:30]2[CH2:34][CH2:33][C@@H:32]([N:35]3[CH2:39][CH2:38][CH2:37][C@@H:36]3[CH3:40])[CH2:31]2)[N:24]=1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][NH:29][C:28]2[C:23]([CH3:22])=[N:24][C:25]([N:30]3[CH2:34][CH2:33][C@@H:32]([N:35]4[CH2:39][CH2:38][CH2:37][C@@H:36]4[CH3:40])[CH2:31]3)=[CH:26][CH:27]=2)[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: CCOC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Product: CCOC(=O)C1(CCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was synthesized in essentially the same manner using the procedures as set forth in Step 1 of Example 1, by condensing 4-(2-oxo-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (66 mg, 0.22 mmol) and 2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine to obtain 111 mg of a crude solid, which was used without purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[CH3:44])[C:38](O)=[O:39].Cl.CN(C)CCCN=C=NCC>CC#N>[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[CH3:44])[C:38]([NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])=[O:39]
Reactant: Cc1ccc(C(=O)O)cc1Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1ccc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1Cl
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3-chloro-4-methyl-benzoic acid (0.4 g, 2.4 mmol) were added. To the reaction mixture, was then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo, and the residue was stirred in H2O (50 mL). A suspension formed and after filtration the solid was reslurried in acetone (20 mL). The suspension was filtered to afford 3-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-methyl-benzamide as a white solid (0.75 g, 79%): mp, 249-251° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.8 min. (97%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.39 (s, 3H), 2.53-2.64 (m, 2H), 2.85-2.96 (m, 1H), 4.94 (d, J=5.8 Hz, 2H), 5.15-5.20 (dd, J=5, 12 Hz, 1H), 7.47-7.97 (m, 6H), 7.82-7.89 (m, 3H), 9.22 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 19.55, 21.97, 30.92, 38.36, 48.86, 121.89, 126.07, 127.15, 127.60, 131.22, 131.52, 133.11, 133.33, 134.80, 139.06, 139.10, 165.13, 166.94, 167.50, 169.81, 172.74. Anal Calcd for C22H18ClN3O5: C, 60.08; H, 4.12; N, 9.55; Cl, 8.06. Found: C, 59.69; H, 4.15; N, 9.60; Cl, 8.08.