Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH:2]=1.S(=O)(=O)(O)O.[C:18](=O)([O-])[O-].[Na+].[Na+]>CO>[C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]([CH3:11])[C:8]([O:10][CH3:18])=[O:9])[CH:2]=1
Reactant: Cc1cccc([C@@H](C)C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](C)c1cccc(C)c1

Procedure:
To (2R)-2-(m-tolyl)propionic acid (12.45 g) were added methanol (14.83 g) and concentrated sulfuric acid (6.46 g), and the mixture was stirred under refluxing for 6 hr. Then, the mixture was neutralized with 10% aqueous sodium carbonate solution, and extracted with hexane. After drying over magnesium sulfate, the residue was concentrated under reduced pressure to give the title compound (12.79 g). The structural property was as described below.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[O:36][CH3:37].C(#N)C>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=3[O:36][CH3:37])[CH2:6][CH2:5]2)=[N:8]1
Reactant: c1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2n[nH]c3ccccc23)CC1
Yield: 83.4 %

Procedure:
A mixture of 3-(4-piperidinyl)-1H-indazole (3.0 g, 15 mmol), K2CO3 (1.6 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 16 hours. The reaction was poured into water and a white solid separated from solution. The solid was collected, dried and afforded 5.1 g of product. Recrystallization from ethanol yielded 3.6 g, the compound, which upon chromatography (preparative HPLC on silica gel, eluting with methylene chloride/methanol-9:1) gave 3.0 g (49%) of an off-white solid. Recrystallization from ethanol afforded the analytically pure 1-[4-[3-[4-(1-1H-indazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=171-173° C.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:16])([F:15])[C:9]1[S:13][CH2:12][C:11](=[O:14])[CH:10]=1.F[B-](F)(F)F.CO[N+:24]1[N:25]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:26]=[C:27]([CH3:29])[CH:28]=1>C(#N)C.O>[CH3:29][C:27]1[C:28]([O:14][C:11]2[CH:10]=[C:9]([C:8]([F:16])([F:15])[F:7])[S:13][CH:12]=2)=[N:24][N:25]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:34][CH:35]=2)[N:26]=1
Reactant: O=C1C=C(C(F)(F)F)SC1
Reactant: CO[n+]1cc(C)nn1-c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1csc(C(F)(F)F)c1
Temperature: 23 °C
Reaction time: 27 h

Procedure:
Potassium tert-butoxide (0.30 g, 2.6 mmol) and 5-trifluoromethylthiophene-3-one (0.44 g, 2.6 mmol) were dissolved in acetonitrile (4 mL). A solution of crude 1-methoxy-4-methyl-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazolium tetrafluoroborate (1:1) (i.e., the product of Example 1, Step B, 0.70 g, 2.0 mmol) in acetonitrile (4 mL) was added at once. The reaction mixture was stirred at 23° C. for 27 h. The reaction mixture was diluted with water (20 mL) and extracted with diethyl ether (2×25 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0 to 5% ethyl acetate in hexanes to afford the title compound (0.105 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.Cl.C>>[N:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:1][C:2]3[CH:3]=[C:4]4[N:8]=[CH:7][NH:6][C:5]4=[CH:9][C:10]=3[N:11]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccncc1
Reactant: Nc1cc2nc[nH]c2cc1N
Agent: Cl
Product: c1cc(-c2nc3cc4[nH]cnc4cc3[nH]2)ccn1

Procedure:
14.8 g. (100 mMole) 5,6-diaminobenzimidazole, 10.7 g. (100 mMole) pyridine-4-aldehyde and 5 ml. concentrated hydrochloric acid are heated to the boil under reflux. After the solution has been clarified with active charcoal, it is evaporated and the residue is digested with a little water. After suction filtration and drying, there are obtained 6.98 g. (29% of theory) of the desired product in the form of colourless crystals of the hydrochloride; m.p.>280° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([F:18])=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([F:18])=[CH:13]3)[C:33]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:34])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc2c(Nc3cccc(Cl)c3)n(-c3cccc(Cl)c3)nc2c1
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(NC1CCCCC1)N(c1cccc(Cl)c1)c1c2ccc(F)cc2nn1-c1cccc(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, (3-chloro-phenyl)-[2-(3-chloro-phenyl)-6-fluoro-2H-indazol-3-yl]-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 3 d under reflux conditions to give the title compound as white solid. MS: m/e=497.3 [M+H+].
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][NH:11][C@H:12]1[CH2:31][N:16]2[C:17]3[C:22]([C:23]([CH2:24][C:25]([O:27]CCC)=[O:26])=[C:15]2[CH2:14][CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3>>[CH:1]1([CH2:6][C:7]([N:11]([CH3:10])[C@H:12]2[CH2:31][N:16]3[C:17]4[C:22]([C:23]([CH2:24][C:25]([OH:27])=[O:26])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC1CCCC1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)CC1CCCC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from cyclopentylacetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 369.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([NH:25][C:26]([CH:2]2[CH2:3][NH:4][CH2:5][CH2:6][N:1]2[C:7]2[C:8]3[N:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cnc2c(N3CCNCC3)ncnc2c1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1)C1CNCCN1c1ncnc2cc(Cl)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 4-(piperazin-1-yl)-7-chloro-pyrido[3,2-d]pyrimidine (1.0 g, 4 mmole) in dichloromethane (40 ml), was added 3-chlorophenyl isocyanate (615 mg, 4 mmole). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, resulting in the pure title compound (1.6 g, yield 99%) as a white solid which was characterized by its mass spectrum as follows: MS (m/z): 403.1 ([M+H]+, 100).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][CH:21]1[CH2:26][CH:25]2[CH2:27][CH:23]([C:24]2([CH3:29])[CH3:28])[CH:22]1[CH2:30][O:31]COC.Cl.CO>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][CH:21]1[CH2:26][CH:25]2[CH2:27][CH:23]([C:24]2([CH3:28])[CH3:29])[CH:22]1[CH2:30][OH:31]
Reactant: COCOCC1C(Nc2cnn(CC(=O)NCc3ccncc3)c(=O)c2Br)CC2CC1C2(C)C
Agent: Cl
Solvent: CO
Product: CC1(C)C2CC(Nc3cnn(CC(=O)NCc4ccncc4)c(=O)c3Br)C(CO)C1C2
Yield: 37 %

Procedure:
rac-2-[5-Bromo-4-({2-[(methoxymethoxy)methyl]-6,6-dimethylbicyclo[3.1.1]hept-3-yl}amino)-6-oxopyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (35 mg, 0.0655 mmol) in 10 mass % hydrogen chloride-methanol (3 mL) was stirred at 60° C. for 1 hour. After completion of the reaction, the reaction solution was evaporated under reduced pressure, and the resulting solid was collected by filtration, then mixed with saturated aqueous sodium hydrogen sulfate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (37% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]([CH3:17])[CH2:15][NH:14][C:13](=[O:18])[C@@H:12]1[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([Cl:34])=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.C(OCC)(=O)C>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH:16]([CH3:17])[CH2:15][N:14]([CH2:23][C:24]2[CH:33]=[C:32]3[C:27]([C:28]([Cl:34])=[CH:29][CH:30]=[N:31]3)=[CH:26][CH:25]=2)[C:13](=[O:18])[C@@H:12]1[CH3:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccnc2cc(CBr)ccc12
Reactant: CC1CNC(=O)[C@H](C)N1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1CN(Cc2ccc3c(Cl)ccnc3c2)C(=O)[C@H](C)N1C(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 95.2 %

Procedure:
(2S,6RS)-2,6-Dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (380 mg, 1.45 mmol) is dissolved in 10 mL of THF and 1 mL of DMF. Sodium hydride (60%, 72 mg, 3.14 mmol) is added at 0° C. and left to stir at room temperature for thirty minutes before 7-bromomethyl-4-chloro-quinoline (257 mg, 1.0 mmol) is added. The reaction is stirred for four hours. Ethyl acetate is added to the mixture, and the reaction is quenched with 3 mL of H2O. The two layers are separated and ethyl acetate (2×30 ml) is used to extract before dried over magnesium sulfate. The residue after filtration and concentration is chromatographed on silica gel (60% EtOAc/Hexane) to give (2S, 6RS)-4-(4-chloro-quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (417 mg, 95% yield). C22H20ClN3O3 MS m/z: 438, 440.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8]([CH3:24])=[C:9]2[C:13](=[C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]=1[CH3:16])[NH:12][CH2:11][CH2:10]2)=[O:5])[CH3:2]>C1(C)C(C)=CC=CC=1.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8]([CH3:24])=[C:9]2[C:13](=[C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])[C:15]=1[CH3:16])[NH:12][CH:11]=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C)c2c(c(NC(=O)C(C)(C)C)c1C)NCC2
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1c(C)c(NC(=O)C(C)(C)C)c2[nH]ccc2c1C
Yield: 90.5 %

Procedure:
N-(5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (1.0 g) was dissolved in xylene (75 ml), and 10% Pd—C. (250 mg) was added, which was followed by refluxing for 1 hr. Pd—C. was filtered off and xylene was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene—CHCl3) to give 0.9 g of N-(5-ethoxycarbonylmethyl-4,6-dimethylindol-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:14]([Cl:27])=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=4)[CH:16]=[CH:17][C:18]=3[Cl:19])[C:8]2=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][CH2:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42]>C1COCC1>[Cl:27][C:14]1[C:13]([CH2:12][CH:9]2[CH2:10][CH2:11][N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]2=[O:28])=[C:18]([Cl:19])[CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: O=C1C(Cc2c(Cl)ccc(-c3ccc(O)cc3)c2Cl)CCN1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: C1CCOC1
Product: O=C(O)CCCOc1ccc(-c2ccc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c2Cl)cc1
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
Place 1-cyclohexyl-3-(2,4-dichloro-4′-hydroxy-biphenyl-3-ylmethyl)-pyrrolidin-2-one (Example 113) (200 mg, 0.5 mmol), sodium iodide (72 mg, 0.5 mmol), and cesium carbonate (1.25 g, 3.8 mmol) in THF (10 mL). Add tert-butyl 4-bromobutanoate (213 mg, 1.0 mmol) and stir at room temperature for 3 hours. Add dichloromethane and wash with water. Dry over sodium sulfate, filter, and concentrate. Dissolve residue in dichloromethane (5 mL) and TFA (5 mL) and stir for 30 minutes. Remove solvent and dissolve product in IM NaOH. The deprotonated carboxylic acid does not go into the aqueous layer. Bring the pH ˜2 with 6M HCl and extract with dichloromethane. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (dichloromethane-5% methanol in dichloromethane) affords 158 mg (66%) the title compound as a brown solid: Mass spectrum (apci) m/z=504.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[C:20]1[C:21]2[C:28]([CH3:29])=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH3:29][C:28]1[C:21]2[C:20]([N:16]3[CH2:15][CH2:14][N:13]([C:11](=[O:12])[CH2:10][C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH2:18][CH2:17]3)=[N:25][CH:24]=[N:23][C:22]=2[NH:26][CH:27]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCN(C(=O)Cc4cccc([N+](=O)[O-])c4)CC3)c12
Temperature: 80 °C

Procedure:
2-(3-Nitrophenyl)-1-(piperazin-1-yl)ethanone from step A (0.32 g, 0.9 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.168 g, 1.0 mmol), and diisopropylethylamine (0.1 ml) were combined in isopropanol and heated at 80° C. for 24 hours. The product was isolated by prep HPLC to give 1-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-(3-nitrophenyl)ethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][NH2:23])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:24]OC(OC)OC.CS(O)(=O)=O.CCOC(C)=O.CCCCCC>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]3[O:21][CH:24]=[N:23][N:22]=3)[N:14]=2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(OC)OC
Reactant: COc1cc(-c2ncn(/C=C\C(=O)NN)n2)cc(C(F)(F)F)c1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(-c2ncn(/C=C\c3nnco3)n2)cc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 10.5 %

Procedure:
In a 50-mL, 3N round-bottomed flask equipped with nitrogen inlet, and a rubber septum, (Z)-3-(3-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.920 g, 1.0 eq.) was dissolved in THF (23 mL, 25V), added trimethylorthoformate (0.328 g, 1.1 eq.) and added methanesulphonic acid (0.161 g, 0.5 eq.). The Reaction mixture was refluxed at 70° C. for 2-3 h. The progress of the reaction was followed by TLC analysis on silica gel with 50% EtOAc-hexane as mobile phase. SM Rf=0.40 and Product Rf=0.5. Reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine solution (3×50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 0.60 g of crude compound. The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate:hexane as mobile phase. The column (5×10 cm) was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection (25-mL fractions) from 35% to 40% ethyl acetate in hexane. Compound started eluting with 35% ethylacetate in hexane. Fraction containing such TLC profile was collected together to obtain pure compound (100 mg), Yield (10.54). 1H NMR (400 MHz, CDCl3) δ 10.25 (S, 1H), 8.5 (S, 1H), 8.04 (S, 1H), 7.89 (S, 1H), 7.51-7.54 (d, J=11.2 Hz, 1H), 7.28 (S, 1H), 7.23 (S, 1H), 6.27-6.30 (d, J=10.8 Hz, 1H), 3.35 (S, 3H): LCMS for C14H10F3N5O2 [M+1]+ 337.3 at 3.60 min (LCMS 93.43%).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([Cl:24])[C:7]2[N:8]([CH:21]=[N:22][CH:23]=2)[C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:20])[CH2:17][C:18]#[N:19])[CH2:12][CH2:11]1)[CH3:3].Br[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2C1CCCCO1.C(N(CC)C(C)C)(C)C.Cl.O1CCOCC1>C(O)C>[Cl:24][C:6]1[C:7]2[N:8]([CH:21]=[N:22][CH:23]=2)[C:9]([N:10]2[CH2:11][CH2:12][N:13]([C:16](=[O:20])[CH2:17][C:18]#[N:19])[CH2:14][CH2:15]2)=[C:4]([CH:2]([NH:1][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][NH:30]3)[CH3:3])[CH:5]=1
Reactant: CC(N)c1cc(Cl)c2cncn2c1N1CCN(C(=O)CC#N)CC1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cncn2c1N1CCN(C(=O)CC#N)CC1
Temperature: 110 °C
Yield: 35.6 %

Procedure:
A mixture of 3-{4-[6-(1-aminoethyl)-8-chloroimidazo[1,5-a]pyridine-5-yl}piperazin-1-yl]-3-oxopropanenitrile (18 mg, 0.052 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (29 mg, 0.10 mmol) and N,N-diisopropylethylamine (27 μL, 0.16 mmol) in ethanol (1.0 mL) was heated at 110° C. overnight. The mixture was evaporated and a 4 M solution of hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) was added. The mixture was evaporated and a 4 M solution of hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) was added. The mixture was evaporated and purified by preparative LCMS (pH 10) to give the desired compound (8.6 mg, 36%). LCMS calculated for C21H22ClN10O (M+H)+: m/z=465.2. found: 464.9.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[C@H:12]2[O:13][CH2:14][C@@H:15]([OH:16])[C@H:11]2[O:10][CH2:9]1.[N+:17]([O:20][C@H:21]([CH2:28][O:29][N+:30]([O-:32])=[O:31])[CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])([O-:19])=[O:18].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[C@H:12]2[O:13][CH2:14][C@@H:15]([O:16][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C@H:21]([O:20][N+:17]([O-:19])=[O:18])[CH2:28][O:29][N+:30]([O-:32])=[O:31])[C@H:11]2[O:10][CH2:9]1
Reactant: O=C(O)CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OC1CCCCO1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
To a solution of (3R,3aR,6R,6aR)-6-(tetrahydro-2H-pyran-2-yloxy)-hexahydrofuro[3,2-b]furan-3-ol (2.96 g, 12.9 mmol) in DCM (40.8 mL) a solution of the crude (S)-5,6-di(nitrooxy)hexanoic acid (3.06 g, 12.85 mmol) (Step D) in DCM (9.15 mL) was added followed by EDAC (3.69 g, 19.28 mmol) and 4-dimethylaminopyridine (175 mg, 1.28 mmol). The reaction mixture was stirred at rt for 16.5 hrs. The solvent was removed under reduced pressure. The crude residue was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 10 to 60%), affording the title product as pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([Cl:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([Cl:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:41][CH:38]2[CH2:39][CH2:40][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)c(Cl)cc2OC)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)c(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(4-chloro-5-fluoro-2-methoxy-phenyl)-methanone (Example 377) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(4-chloro-5-fluoro-2-methoxy-phenyl)-methanone as a white solid. MS (M+H)+, 458.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[N:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3]>C(O)C.[Pd]>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[N:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: COC(=O)c1cnc(C2=CCN(C(=O)OC(C)(C)C)CC2)cn1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cnc(C2CCN(C(=O)OC(C)(C)C)CC2)cn1
Reaction time: 6 h
Yield: 68.8 %

Procedure:
Palladium, 10% on carbon (21 mg, 0.20 mmol) and methyl 5-[1-[(2-methylpropan-2-yl)oxycarbonyl]-3,6-dihydro-2H-pyridin-4-yl]pyrazine-2-carboxylate (183 mg, 0.57 mmol) in ethanol (5.73 mL) was stirred under an atmosphere of hydrogen at ambient temperature and atmospheric pressure for 6 h. The reaction mixture was filtered through celite and concentrated under reduced pressure to give a yellow oil. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 5-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]pyrazine-2-carboxylate (126 mg, 68%) as a yellow oil.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.O=C1CC2C(=CC=C(/C=C/C(O)=O)C=2)N1.[CH3:34][NH:35][CH2:36][C:37]1[O:38][C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[CH:41]=1.CC1NC2C(C=1CNC)=CC=CC=2>>[O:38]1[C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[CH:41]=[C:37]1[CH2:36][N:35]([CH3:34])[C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]1[CH:9]=[N:10][C:11]2[NH:12][C:3](=[O:2])[CH2:4][CH2:5][C:6]=2[CH:7]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1cc2ccccc2o1
Agent: CNCc1c(C)[nH]c2ccccc12
Agent: Cl
Agent: O=C(O)/C=C/c1ccc2c(c1)CC(=O)N2
Product: CN(Cc1cc2ccccc2o1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 87.8 %

Procedure:
According to the procedure of Example 4, except substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt (1.60 g, 6.3 mmole) for the (E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt, and substituting 2-(methylaminomethyl)benzofuran (1.20 g, 6.9 mmole) for the 2-methyl-3-(methylaminomethyl)indole, the title compound (2.0 g, 90%) was prepared as a tan solid: MS (ES) m/e 363 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>C1COCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH2:26][NH:40][CH2:39][CH2:38][O:37][CH3:36])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(CCl)cn4c3-c3ccccc3)cc2)CCC1
Solvent: C1CCOC1
Product: COCCNCc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Temperature: 110 °C

Procedure:
A mixture of {1-[4-(6-chloromethyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (103 mg) and 2-methoxyethylamine (31 mg, 0.035 mL) in THF (1.1 mL) was heated at 110° C. under microwave irradiation for 1 hour. On cooling, the reaction mixture was concentrated in vacuo to give the crude title compound which was used in the next step without further purification.