Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[S:22][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[N:20][C:19]=2[CH3:27])=[N:16][CH:17]=1>N1C=CC=CC=1>[CH3:27][C:19]1[N:20]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:22][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:17][N:16]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(N)cn2)s1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(C)c(-c2ccc(NS(=O)(=O)c3ccccc3)cn2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzenesulfonyl chloride (0.062 mL) was added to a stirred mixture of N-[5-(5-aminopyridin-2-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (100 mg) and pyridine (1 mL) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated and the residue was triturated under methanol. The resultant precipitate was filtered off, washed in turn with methanol and diethyl ether and dried. There was thus obtained the title compound (85 mg); 1H NMR Spectrum: (DMSOd6) 2.13 (s, 3H), 2.47 (s, 3H), 7.55-7.65 (m, 5H), 7.80 (m, 2H), 8.26 (m, 1H), 10.58 (s, 1H), 12.05 (s, 1H); Mass Spectrum: M+H+ 389.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:16]I>CCO>[CH3:16][S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1
Reactant: CI
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Solvent: CCO
Product: CSc1nnc(-c2ccc3[nH]cnc3c2)o1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and methyliodide (0.093 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH2:10][CH3:11])[CH:3]=1.Br[CH2:13][CH2:14][CH3:15].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][CH3:15])=[C:4]([O:9][CH2:10][CH3:11])[CH:3]=1
Reactant: CCCBr
Reactant: CCOc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(Br)cc1OCC
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A suspension of 4-bromo-2-ethoxyphenol (8 g), 1-bromopropane (4 ml), sodium iodide (5.5 g) and potassium carbonate (10.2 g) in DMF (10 ml) was stirred under nitrogen atmosphere at 75° C. overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was distilled under reduced pressure to give 1-bromo-3-ethoxy-4-propoxybenzene (8.5 g) as pale yellow oil.
Reaction SMILES: [ClH:1].C(N1CCC([N:14]2[C:26]3[C:25]4[CH:24]=[C:23](C(N5CCC(COCC)CC5)=O)[C:22](C)=[CH:21][C:20]=4[NH:19][C:18](=[O:40])[C:17]=3[CH:16]=[N:15]2)C1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[ClH:1].[NH:14]1[C:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:19][C:18](=[O:40])[C:17]=2[CH:16]=[N:15]1
Reactant: CCOCC1CCN(C(=O)c2cc3c(cc2C)[nH]c(=O)c2cnn(C4CCN(Cc5ccccc5)C4)c23)CC1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]c2ccccc2c2[nH]ncc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 224 mg of 1-(1-benzylpyrrolidin-3-yl)-8-{[4-(ethoxymethyl)piperidin-1-yl]carbonyl}-7-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one hydrochloride and 9 mL of methanol was added 23 mg of a 10% palladium hydroxide/carbon powder, followed by stirring at room temperature for 20 hours under a hydrogen atmosphere of 3 atm. The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by reverse phase column chromatography (acetonitrile/water=0/100-35/65). The obtained compound was dissolved in 4 mL of methanol, and 1 mL of a 4 M hydrogen chloride-ethyl acetate solution was added thereto, followed by stirring for 1 hour. Then, the solvent was evaporated under reduced pressure and the solid was collected by filtration, washed with diethyl ether, and then dried under reduced pressure to obtain 180 mg of 8-{[4-(ethoxymethyl)piperidin-1-yl]carbonyl}-7-methyl-1-pyrrolidin-3-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one hydrochloride as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23]O)=[CH:14]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:23][CH2:22][C:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][CH:14]=3)[N:11]=[C:4]2[N:3]=1
Reactant: OCCc1c[nH]c2ccccc12
Reactant: Cc1cc(C)n2nc(S)nc2n1
Product: Cc1cc(C)n2nc(SCCc3c[nH]c4ccccc34)nc2n1
Yield: 54 %

Procedure:
The title compound was prepared according to the experimentals described for Example 9 above from 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol and 2-(1H-indol-3-yl)ethanol in 54% yield; EM (calc.): 323.1; MS (ESI) m/e: 324.1 (M+H)+.
Reaction SMILES: CS[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1>C(CN)O>[O:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[NH:7][CH2:6][CH2:5][OH:4]
Reactant: CSc1nc2ccccc2o1
Solvent: NCCO
Product: OCCNc1nc2ccccc2o1
Temperature: 100 °C

Procedure:
To 2-methylsulfanyl-benzooxazole [compound of Step I] (25 g, 150 mmol), ethanolamine (253 g, 250 mL) was added and the reaction mixture was heated at 100° C. for 1.5 hours. The reaction mixture was poured on crushed ice-water mixture and extracted with ethyl acetate (3×1 L). The ethyl acetate layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give 2-(benzooxazol-2-ylamino)-ethanol.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([N:43]2[N:47]=[CH:46][CH:45]=[N:44]2)[C:35]=1[C:36](O)=[O:37].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:36]([C:35]4[C:39]([N:43]5[N:47]=[CH:46][CH:45]=[N:44]5)=[CH:40][CH:41]=[CH:42][C:34]=4[F:33])=[O:37])[CH2:15]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: Cc1cnc(C)c(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cnc(C)c(N2C[C@@H]3CCN(C(=O)c4c(F)cccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(3,6-Dimethyl-pyrazin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 10) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-Fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C21H22FN7O, 407.45; m/z found 408.2 [M+H]+. 1H NMR (CD3OD): 7.96-7.23 (m, 6H), 4.50-4.44 (m, 1H), 4.31-4.19 (m, 2H), 4.11-3.77 (m, 3H), 3.62-3.42 (m, 1H), 2.86-2.77 (m, 1H), 2.40-2.36 (m, 3H), 2.31-2.05 (m, 2H), 2.04-1.92 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=2[C:5]([F:13])=[C:4]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:3]=1.BrC1C(OC)=CC(NCC2C=CC3N=C(SC)SC=3C=2)=C([N+]([O-])=O)C=1>>[F:1][C:2]1[C:7]2[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=2[C:5]([F:13])=[C:4]([CH2:14][NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:3]=1
Reactant: CSc1nc2c(F)cc(CNc3ncccc3[N+](=O)[O-])c(F)c2s1
Agent: COc1cc(NCc2ccc3nc(SC)sc3c2)c([N+](=O)[O-])cc1Br
Product: CSc1nc2c(F)cc(CNc3ncccc3N)c(F)c2s1

Procedure:
N2-((4,7-Difluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine was synthesized as a yellow solid (190 mg) using a procedure analogous to that described in Step 2 of Example 41, substituting N-((4,7-difluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amine from the previous step for 4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline used in Example 41. LCMS (ESI) m/z 339 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][CH3:10])=[N:4][CH:5]=[N:6][C:7]=1O.P(Cl)(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[Cl:13][C:7]1[C:2]([Cl:1])=[C:3]([CH2:9][CH3:10])[N:4]=[CH:5][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1ncnc(O)c1Cl
Solvent: Cc1ccccc1
Product: CCc1ncnc(Cl)c1Cl
Temperature: 100 °C
Reaction time: 1.33 h

Procedure:
A mixture of 3.19 g (0.020 mol) of 5-chloro-4-ethyl-6-hydroxypyrimidine, 15.33 g (0.10 mol) of phosphoryl chloride and 45 g of toluene was heated to 100° C. and stirred at this temperature for 80 minutes. The excess phosphoryl chloride and the toluene were distilled off and the residue was mixed with 30 ml of dichloromethane and 20 ml of water. The mixture was refluxed after 30 minutes, extracted with 3×30 ml of dichloromethane and dried on sodium sulfate. The dichloromethane solution was evaporated and the residue was distilled at 125° C./12 torr in the bulb tube apparatus. The following data concerns the product of this example:
Reaction SMILES: BrCCBr.[Mg].Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:9]([O:22][CH3:23])[CH:8]=1.FC1C=CC=CC=1COC1C=CC=CC=1OC.[O:41]=[C:42]1[N:46]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:45]([C:54]([O:56][CH3:57])=[O:55])[CH2:44][CH2:43]1>C1COCC1.C(OCC)C.C(O)(C)C>[CH3:53][C:50]([O:49][C:47]([NH:46][C@@H:45]([CH2:44][CH2:43][C:42]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:9]([O:22][CH3:23])[CH:8]=1)=[O:41])[C:54]([O:56][CH3:57])=[O:55])=[O:48])([CH3:51])[CH3:52]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: COc1cc(Br)ccc1OCc1ccccc1F
Agent: COc1ccccc1OCc1ccccc1F
Agent: [Mg]
Solvent: CCOCC
Solvent: CC(C)O
Solvent: BrCCBr
Product: COC(=O)[C@H](CCC(=O)c1ccc(OCc2ccccc2F)c(OC)c1)NC(=O)OC(C)(C)C
Temperature: -65 °C
Reaction time: 3.5 h
Yield: 46.1 %

Procedure:
1,2-Dibromoethane (106 μL, 232 mg, 1.233 mmol) was added to a suspension of magnesium (300 mg, 12.33 mmol) in dry THF (3 mL). Then a solution of 4-bromo-1-{[(2-fluorophenyl)methyl]oxy}-2-(methyloxy)benzene (D54, 2.40 g, 8.22 mmol) in dry THF (17 ml) was added dropwise. The mixture was heated under reflux for 1.5 h. The Grignard formation was followed via HPLC (Rt(HPLC, 1-fluoro-2-{[(2-(methyloxy)phenyl]oxy}methyl)benzene): 5.59 min, Rt (HPLC, D54): 6.24 min). When the reaction stopped, additional 1,2-dibromoethane (0.1 eq) was added. After Grignard formation was complete, the mixture was added dropwise to a solution of 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D1, 1 g, 4.11 mmol) in dry THF (20 ml) at −65° C. Stirring at −65° C. was continued for 3.5 h. Then isopropanol and diethylether were added, the organic layer was washed with aqueous ammonium chloride solution, dried (Na2SO4) and evaporated. The residue was purified with flash chromatography using a cyclohexanes/ethyl acetate (40% to 100%) gradient to afford the title compound (900 mg, 46%). MS: (ES/+) m/z: 376 [M-BOC+], C25H30FNO7 requires 475; UPLC: 0.84 min, m/z: 476 [MH+], 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.6 (m, 2H), 7.4 (m, 2H), 7.3-7.2 (m, 4H), 5.2 (s, 2H), 4.1 (m, 1H), 3.8 (s, 3H), 3.6 (s, 3H), 3.2-3.0 (m, 2H), 2.1-2.0 (m, 1H), 1.9 (m, 1H), 1.4 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][N:20]3[C:24](=[O:25])[CH2:23][O:22][C:21]3=[O:26])[CH2:14][CH2:13]1)=[N:7]2.[CH3:27][NH2:28]>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][NH:20][C:21](=[O:26])[O:22][CH2:23][C:24]([NH:28][CH3:27])=[O:25])[CH2:14][CH2:13]1)=[N:7]2
Reactant: O=C1COC(=O)N1CCC1CCN(c2ccc3c(Cl)cccc3n2)CC1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCC1CCN(c2ccc3c(Cl)cccc3n2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.5). Starting with 6.40 g (17.12 mmol) of 3-{2-[1-(5-chloro-2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, obtained in step 15.3, and 60 ml (119.84 mmol) of a solution (2M) of methylamine in tetrahydrofuran, and after chromatography on silica gel, eluting with a 98/2 and then 96/4 mixture of dichloromethane and methanol, followed by crystallization from diisopropyl ether, 5.14 g of product are obtained in the form of a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[C:28]#[CH:29].O>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[N:13]([CH2:29][C:28]#[CH:27])[N:12]=1
Reactant: C#CCBr
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCn1nc(-c2ccc3ccccc3c2)c2c(N)ncnc21
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and propargylbromide were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 300.1, found 300.2
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@@H:8]([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].CCN(CC)CC.O>C(Cl)Cl>[C:13]([O:10][CH2:9][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])[CH3:11])(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H](COC(=O)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the commercially available tert-butyl[(1S)-2-hydroxy-1-methylethyl]carbamate (1.0 eq.) in DCM (0.19M), pivaloyl chloride (1.1 eq.) and Et3N (1.1 eq.) were added. The reaction mixture was stirred at RT for 48 h, then water was added and the organic phase was separated and washed with 10% aqueous citric acid. The residue was purified by column chromatography on silica gel eluting with 92:8 PE/EtOAc.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:33])[N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:33])[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2cc(C)ccc2n(Cc2ccc(F)cc2)c1=O
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2Cc1ccc(F)cc1
Yield: 92.2 %

Procedure:
Cyclohexylamine (3.22 mL, 28.14 mmol) was added to a solution of Compound 16 (5.0 g, 14.07 mmol) in toluene (50 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 5.3 g (93%) of yellow solids. M.P. 156° C. 1H NMR (DMSO-d6): δ 1.24 (m, 1H), 1.37 (m, 4H), 1.57 (m, 1H), 1.68 (m, 2H), 1.88 (m, 2H), 2.36 (s, 3H), 3.87 (m, 1H), 5.49 (s, 2H), 7.11 (m, 2H), 7.22 (m, 2H), 7.36 (d, J=8.7 Hz, 1H), 7.51 (dd, J=1.6, 8.7 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 10.39 (s, 1H). EIMS m/z 409 (M+1), 431 (M+23).
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([O:14][C:15]([N:17]1[CH2:24][CH2:23][NH:22][CH2:21][C:18]21[CH2:20][CH2:19]2)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:25]1[CH2:28][C:27](=O)[CH2:26]1.CCN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:7]([O:14][C:15]([N:17]1[CH2:24][CH2:23][N:22]([CH:27]2[CH2:28][O:25][CH2:26]2)[CH2:21][C:18]21[CH2:20][CH2:19]2)=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC12CC2
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)N1CCN(C2COC2)CC12CC2
Reaction time: 68 h

Procedure:
A mixture of 4,7-diazaspiro[2.5]octane-4-carboxylic acid benzyl ester oxalate (200 mg, 0.59 mmol), oxetan-3-one (50 mg, 0.69 mmol), NEt3 (82 μL, 0.59 mmol) and 4 Å powdered molecular sieves (1.0 g) in DCE (10 mL) was stirred at r.t. for 2 h before the addition of sodium triacetoxyborohydride (164 mg, 0.78 mmol). The resulting mixture was stirred for 68 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound. LCMS (method H): RT 2.01 min, [M+H]+ 303.3
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][C:17]([O:19]C)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Mg]Br.C(OCC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][C:17]2=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCC2=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 19.6 %

Procedure:
To a solution of 4-(2-methoxycarbonyl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.4 g, 12.0 mmol) in anhydrous THF (75 mL) was slowly added a solution of methyl magnesium bromide in diethyl ether (3 M, 6 mL, 18 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 h, then allowed to warm to RT and stirring was continued for 72 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between EtOAc and an aqueous solution of ammonium chloride. The organic layer was separated and washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-(2-oxo-azetidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (598 mg, 20%). To a solution of 4-(2-oxo-azetidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (595 mg, 2.34 mmol) in DCM (6 mL) was added TFA (2 mL). The resulting mixture was stirred at RT for 1.5 h, then concentrated in vacuo. The resultant residue was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a pale yellow solid (325 mg, 90%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([NH:20][C:21]2[S:22][C:23]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH2:27][C:28]=3[N:29]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)(=[O:3])[CH3:2].Cl>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([NH:20][C:21]2[S:22][C:23]3[CH2:24][NH:25][CH2:26][CH2:27][C:28]=3[N:29]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2cc(Nc3nc4c(s3)CN(C(=O)OC(C)(C)C)CC4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)OCc1c(-c2cc(Nc3nc4c(s3)CNCC4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of 233b (220 mg, 0.308 mmol) in ethyl acetate (5 mL) was added a solution of HCl in ethyl acetate (0.123 mL, 2.5M, 0.308 mmol). The mixture was stirred at room temperature for 1 h. It was then concentrated under reduced pressure to afford 233c (180 mg, crude), which was used directly for next step without further purification. MS-ESI: [M+H]+ 614.3
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[N:23]=[CH:24][N:25]([CH2:27][CH2:28][O:29]C6CCCCO6)[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:36]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.O1CCOCC1>CCO>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[N:23]=[CH:24][N:25]([CH2:27][CH2:28][OH:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:36]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cn(CCOC4CCCCO4)cn3)cc1OCC2
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cn(CCO)cn3)cc1OCC2
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To a solution of 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (250 mg, 0.51 mmol) in EtOH (15 mL) was added a solution of hydrogen chloride in dioxane (1.28 mL, 5.1 mmol). The mixture was refluxed for 2 h, cooled to room temperature and concentrated. The resulting precipitates were washed with EtOAc to give 207 as a yellow solid (115.2 mg, yield 56%). 1H NMR (Methane-d4, 400 MHz): δ9.12 (d, J=1.2 Hz, 1H), 8.78 (s, 1H), 8.65 (d, J=8.4 Hz, 1H), 8.28 (s, 1H), 8.17 (d, J=1.2 Hz, 1H), 7.58-7.53 (m, 2H), 5.85-5.78 (m, 1H), 4.71-4.63 (m, 4H), 4.41 (t, J=5.2 Hz, 2H), 3.96 (t, J=5.2 Hz, 2H), 1.66 (d, J=6.8 Hz, 6H). MS: (ESI, m/z)=406 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24]([Cl:31])[C:23]=1F>>[Cl:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24]([Cl:31])[C:23]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[N:9]=[C:10]([CH3:18])[C:11]=12
Reactant: O=[N+]([O-])c1cc(Cl)c(F)c(Cl)c1
Reactant: COc1ccc(Cn2nc(C)c3c(O)ccnc32)cc1
Product: COc1ccc(Cn2nc(C)c3c(Oc4c(Cl)cc([N+](=O)[O-])cc4Cl)ccnc32)cc1
Yield: 76.2 %

Procedure:
Prepared from 1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (0.150 g, 0.557 mmol; prepared as in Example 5, Step B) and 1,3-dichloro-2-fluoro-5-nitrobenzene (0.117 g, 0.557 mmol), according to the procedure of Example 13, Step A. The crude product was purified Biotage 40S column eluting with 3:1 hexane/EtOAc then EtOAc to obtain the product (195 mg, 73%) as an off white solid. 1H NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.29 (d, J=5.5 Hz, 1H), 7.37 (d, J=8.6 Hz, 2H), 6.85 (d, J=9.0 Hz, 2H), 5.93 (d, J=5.5 Hz, 1H), 5.58 (s, 2H), 3.77 (s, 3H), 2.75 (s, 3H). LRMS (esi pos) m/e 460 (M+1).
Reaction SMILES: C(O)(C)(C)C.[K].[CH3:7][C:8]1[C:12]([CH:13]=[O:14])=[CH:11][NH:10][N:9]=1.F[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=1>CN(C)C=O.C(OCC)(=O)C>[F:22][C:21]1[C:16]([N:10]2[CH:11]=[C:12]([CH:13]=[O:14])[C:8]([CH3:7])=[N:9]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1n[nH]cc1C=O
Reactant: Fc1cccnc1F
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: Cc1nn(-c2ncccc2F)cc1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.6 %

Procedure:
Potassium t-Butyl alcohol (29.25 g, 260.68 mmol) is added to a solution of 3-methyl-1H-pyrazole-4-carbaldehyde (26.00 g, 236.12 mmol) in dimethylformamide (250 mL) cooled with an aqueous bath. The mixture is stirred at room temperature for 10 min. Then, 2,3-difluoropyridine (25 g, 217.24 mmol) is added and the mixture is stirred at room temperature for 20 hr. The mixture is poured over an ice/water mixture and extracted in ethyl acetate (3×20 mL). Organics are dried over magnesium sulfate and solvent evaporated in vacuo. The residue is purified by silica gel chromatography using as eluent hexane/isopropyl alcohol to afford a crude material with residual dimethylformamide. The material is then dissolved in ethyl acetate (100 mL) and washed with water (3×20 mL). Aqueous phase is extracted with ethyl acetate (2×20 mL). Combined organics are dried over sodium sulfate and concentrated to give 19 g of the title compound. MS (m/z): 206 (M+1).