Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:31](=[O:32])[N:6]2[C:7]([C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])=[C:8]([C:10]3[S:14][C:13]4=[CH:15][N:16]=[CH:17][N:12]4[CH:11]=3)[CH2:9][C@H:5]12)[CH3:3].P([O-])([O-])([O-])=O>C1COCC1.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:31](=[O:32])[N:6]2[C:7]([C:18]([OH:20])=[O:19])=[C:8]([C:10]3[S:14][C:13]4=[CH:15][N:16]=[CH:17][N:12]4[CH:11]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cncc4s3)C[C@H]12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(c3cn4cncc4s3)C[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
To a solution of 41 mg of 4-nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate in 2 ml of THF and 2 ml of {fraction (1/15)} M phosphate buffer (pH 6.8) was added 61 mg of 10% Pd-C. The reactor was purged with hydrogen, and the reaction mixture was stirred at room temperature for 2 hours. The catalyst was removed by filtration on Celite and washed with water. The filtrate was washed with ethyl acetate, and the aqueous layer was purified by column chromatography on DIAION HP-20 to give 5.7 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[N:25]1([C:30]2[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[CH2:38]O)=[CH:32][CH:31]=2)[CH:29]=[CH:28][N:27]=[CH:26]1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:38]/[CH:37]=[CH:36]/[C:33]1[CH:32]=[CH:31][C:30]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:35][CH:34]=1)=[O:9]
Reactant: OC/C=C/c1ccc(-n2ccnc2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(-n3ccnc3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 200 mg (1 mM) of (E)-3-{4-(1-imidazolyl)phenyl}-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced was filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 494 mg (96%).
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH2:42][CH2:43][O:44][CH2:45][CH:46]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.[H][H]>CO>[OH:31][C:30]1[C:25](=[O:24])[NH:26][N:27]=[C:28]([CH2:39][CH2:40][CH:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)[CH:29]=1
Reactant: [H][H]
Reactant: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)C1=CCOCC1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CO
Product: O=c1[nH]nc(CCC2CCOCC2)cc1O
Yield: 16 %

Procedure:
Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(3,6-dihydro-2H-pyran-4-yl)ethynyl]pyridazine (Intermediate 60) except that the pressure of hydrogen gas was 200 psi at room temperature overnight and the solvent used for the hydrogenation was methanol and the product was purified by column chromatography (silica gel, eluting with 0-5% methanol in dichloromethane to afford the title compound (0.1 g, 16% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:13]2=[O:28])[S:5][C:6]=1[C:7](OCC)=[O:8].[BH4-].[Li+].CO>>[OH:8][CH2:7][C:6]1[S:5][C:4]([N:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:22][CH:23]=3)[C:13]2=[O:28])=[N:3][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1CO
Temperature: 25 °C
Reaction time: 22 h
Yield: 56 %

Procedure:
To a solution of ethyl 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)-imidazolidin-1-yl)thiazole-5-carboxylate (1.00 g, 2.41 mmol) in tetrahedrofuran (50 mL) was added lithium borohydride (2.7 mL of 2.0 M solution in tetrahedrofuran, 5.4 mmol) and methanol (0.10 mL, 2.47 mmol). The reaction mixture was stirred for 22 hours at ambient temperature and quenched with water. The resulting solution was extracted with chloroform and washed with water. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by column chromatography to afford the title compound in 56% yield (0.51 g): mp 153-154° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.59 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 4.69 (d, J=5.1 Hz, 2H), 4.52 (s, 2H), 4.13-4.02 (m, 2H), 3.45-3.40 (m, 2H), 2.26 (s, 3H); MS (ES+) m/z 372.1 (M+1).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=3)[CH:20]=2)[C@@H:13]([CH3:32])[CH2:12]1)=O)C1C=CC=CC=1.[NH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1>>[CH3:32][C@@H:13]1[C@H:14]([NH:17][CH2:18][C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:33][CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=4)[N:26]=3)[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:16][NH:11][CH2:12]1
Reactant: NCCc1ccc(O)cc1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1NCc1cccc(-c2ccnc(Cl)n2)c1
Product: C[C@H]1CNCC[C@H]1NCc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 136 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G3. LC-MS showed the product had the expected M+H+ of 418. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.63 (s, 1H) 8.36 (d, 2H) 7.95 (d, 1H) 7.75 (t, 1H) 7.67 (d, 1H) 7.15 (d, 2H) 6.71 (d, 2H) 4.50 (s, 2H) 3.96 (m, 1H) 3.80 (m, 1H) 3.72 (m, 1H) 3.56 (d, 1H) 3.34 (d, 1H) 3.20 (t, 2H) 2.96 (t, 2H) 2.80 (m, 1H) 2.38 (dd, 2H) 1.36 (d, 3H).
Reaction SMILES: C(OC[N:10]1[CH:14]=[C:13]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26]([C:32]5[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([NH:40][CH:41]([CH3:43])[CH3:42])[CH:33]=5)[N:27]=[C:28]([CH:29]([CH3:31])[CH3:30])[C:21]=34)[CH:19]=2)[CH:12]=[N:11]1)C1C=CC=CC=1.C(OCN1C=C(C2N=CN(C3C=CN=C4N(C5C(Br)=C(C=CC=5)C#N)N=C(C(C)C)C=34)C=2)C=N1)C1C=CC=CC=1.C(N)(C)C.O[C@H]1CC[C@H](N)CC1.[OH-].[Na+]>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[NH:10]1[CH:14]=[C:13]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26]([C:32]5[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([NH:40][CH:41]([CH3:43])[CH3:42])[CH:33]=5)[N:27]=[C:28]([CH:29]([CH3:31])[CH3:30])[C:21]=34)[CH:19]=2)[CH:12]=[N:11]1
Reactant: CC(C)Nc1cc(-n2nc(C(C)C)c3c(-n4cnc(-c5cnn(COCc6ccccc6)c5)c4)ccnc32)ccc1C#N
Agent: CC(C)c1nn(-c2cccc(C#N)c2Br)c2nccc(-n3cnc(-c4cnn(COCc5ccccc5)c4)c3)c12
Agent: N[C@H]1CC[C@H](O)CC1
Agent: [Na+]
Solvent: CC(C)N
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)Nc1cc(-n2nc(C(C)C)c3c(-n4cnc(-c5cn[nH]c5)c4)ccnc32)ccc1C#N
Temperature: 70 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
According to Example 1(6), 4-{4-(4-(1-(benzyloxymethyl)-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isopropylamino)benzonitrile (65%) was prepared using compound (143a) and isopropylamine instead of compound (1e) and trans-4-hydroxycyclohexylamine, respectively, and this 4-{4-(4-(1-(benzyloxymethyl)-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isopropylamino)benzonitrile was dissolved in anisole and trifluoroacetic acid, followed by stirring at 70° C. for 3 hr. The reaction solution was distributed between chloroform and a 2 M aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled away to obtain 4-{4-(4-(1H-pyrazol-4-yl)-1H-imidazol-1-yl)-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isopropylamino)benzonitrile, which was used in the subsequent reaction without being purified. Lastly, according to Example 1(7), compound (143) (the second stage yield: 43%) was prepared as a white solid using 4-{4-(4-(1H-pyrazol-4-yl)-1H-imidazol-1-yl)-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isopropylamino)benzonitrile instead of compound (1f).
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].[O:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([CH:21]([CH3:25])[C:22](Cl)=[O:23])=[CH:20][C:7]1=2.CCCCCC>N1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[O:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([CH:21]([CH3:25])[C:22]([N:3]([OH:4])[CH3:2])=[O:23])=[CH:20][C:7]1=2
Reactant: CNO
Reactant: CC(C(=O)Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C(=O)N(C)O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Yield: 65.1 %

Procedure:
A stirred solution of 16.6 g of N-methylhydroxylamine hydrochloride in 400 ml of dry pyridine was chilled and treated dropwise over several minutes with a solution of 15.7 g of 2-(6,11-dihydro11oxodibenz[b,e]oxepin-2-yl)propionyl chloride in 500 ml of tetrahydrofuran. The solution was allowed to equilibrate to room temperature with continued stirring. Thin layer analysis (silica gel, 30% hexane in ethyl acetate) indicated reaction completion after 5 hours. Pyridine and tetrahydrofuran were removed in vacuo and the resulting mixture was partitioned against a total of 700 ml of methylene chloride and 2000 ml of 10% HCl (pH of aqueous layers <1). The organic phase was washed with 500 ml of water. The dried (Na2SO4) organic phase was concentrated in vacuo to an oil. Thin layer analysis indicated a mixture, which was separated via preparative HPLC to give 10.58 g of the product, 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-methylpropanamide, as an oil.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][C:2]1=[O:12].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[CH3:18][O:17][C:15]([CH2:14][N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][C:2]1=[O:12])=[O:16]
Reactant: COC(=O)CBr
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Product: COC(=O)Cn1c2c(ccc1=O)C(=O)CCC2

Procedure:
Prepared analogously to Example 29 from 7,8-dihydro- 2,5(1H,6H)-quinolinedione and methyl bromoacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(-c2cncs2)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1cc(Cl)cc(-c2cncs2)c1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-(3-chloro-5-nitrophenyl)thiazole (0.120 g, 0.499 mmol) inethanol (5 mL) was added tin dichloride (0.9555 g, 4.986 mmol). The mixture was stirred at 90° C. for 1.5 h. After cooling to rt, sat. NaHCO3 (aq) was added dropwise to adjust the pH to 9-10. The resulting suspension was filtered through a Celite pad. The filtrate was concentrated to dryness in vacuo to afford the title compound, which was used directly in the next step without purification. 1H-NMR (CD3OD, 400 MHz): δ=6.67 (t, J=2.0 Hz, 1H), 6.85 (t, J=1.6 Hz, 1H), 6.88 (t, J=1.6 Hz, 1H), 8.10 (s, 1H), 8.94 (s, 1H). MS (ES+): m/z 211.10 (MH+, 35Cl), 213.12 (MH+, 37Cl). HPLC: tR=2.92 min (ZQ2000, polar—5 min).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CNCCN1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2-piperazinone (Alfa) to give the title compound. HR-MS (ES, m/z) calculated for C33H38Cl2N5O3 [(M+H)+] 622.2346, observed 622.2346.
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:9]([O:12][CH2:13][C:14](=O)[CH2:15]Cl)(=[O:11])[CH3:10]>C1(C)C=CC=CC=1>[C:9]([O:12][CH2:13][C:14]1[N:1]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:8][CH:15]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(=O)CCl
Reactant: CCOC(=O)C(N)=S
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(COC(C)=O)cs1
Temperature: 100 °C

Procedure:
Ethyl 2-amino-2-thioxoacetate (0.5 g, 3.75 mmol) and 3-chloro-2-oxopropyl acetate (0.565 g, 3.75 mmol) were dissolved in toluene (10 mL) and heated in a microwave at 100° C. for 1 h then heated for a further 3 h at 120° C. Cooled to RT, evaporated in vacuo and purified by chromatography on silica with 20% EtOAc/isohexane as eluent to afford the sub-title compound as a pale yellow solid. Yield: 0.7 g
Reaction SMILES: OC(C(F)(F)F)=O.[CH2:8]1[C:11]2([CH2:15][CH2:14][CH2:13][NH:12]2)[CH2:10][O:9]1.C(N(CC)CC)C.[C:23]1([C:29]2[O:33][C:32]([C:34]([N:36]3[CH2:39][CH:38]([O:40][C:41]4[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=4)[CH2:37]3)=[O:35])=[N:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[CH2:10]1[C:11]2([CH2:15][CH2:14][CH2:13][N:12]2[CH2:45][C:44]2[CH:43]=[CH:42][C:41]([O:40][CH:38]3[CH2:37][N:36]([C:34]([C:32]4[O:33][C:29]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[N:30][N:31]=4)=[O:35])[CH2:39]3)=[CH:48][CH:47]=2)[CH2:8][O:9]1
Reactant: C1CNC2(C1)COC2
Reactant: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Oc2ccc(CN3CCCC34COC4)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
2-Oxa-5-azaspiro[3.4]octane TFA salt (0.16 g, 67%, 0.47 mmol) was dissolved in dichloromethane (3 ml). Triethyl amine (0.119 ml, 0.86 mmol) was added, followed by 4-(1-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.15 g, 0.43 mmol) and finally sodium triacetoxyhydroborate (0.182 g, 0.86 mmol). The mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with dichloromethane (10 ml) was added and shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded a colourless residue, which was purified by preparative reverse-phase HPLC at pH 10 to give 0.140 g (73%) of the desired product as a solid. 1H NMR (600 MHz, DMSO) δ 1.62 (dt, 2H), 2.09-2.15 (m, 2H), 2.47-2.5 (m, 2H), 3.90 (d, 2H), 4.08-4.14 (m, 1H), 4.43 (d, 2H), 4.54-4.59 (min, 1H), 4.64 (ddd, 1H), 4.80 (d, 2H), 5.09-5.13 (m, 1H), 5.16 (ddd, 1H), 6.87 (d, 2H), 7.30 (d, 2H), 7.64-7.74 (m, 3H), 8.07-8.13 (m, 2H). MS (APCI+) m/z 447.2 [M+H]+, LC purity: 94%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([CH:28]2[CH2:30][O:29]2)[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1.[CH:32]([NH2:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.CO>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([CH:28]([OH:29])[CH2:30][NH:35][CH:32]([CH3:34])[CH3:33])[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1C1CO1
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1C(O)CNC(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
N-[1-(5-chloro-2-methoxy-4-methyl-3-oxiran-2-ylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (140.0 mg, 0.32 mmol) was stirred in methylene chloride (1.1 mL). Isopropylamine (124 μL, 1.6 mmol) and DIPEA (282 pt, 1.62 mmol) were added. The mixture was stirred at 80° C. overnight. Methanol was added and purification by preparative LC/MS (pH 10) gave the desired compound (12.9 mg, 8%). LCMS calculated for C25H36ClN6O3 (M+H)+: m/z=503.3. found: 503.1.
Reaction SMILES: [CH2:1]([CH:3]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:7]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:6]=2[NH:5][C:4]1=[O:24])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([CH:3]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:7]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:6]=2[N:5]([CH3:25])[C:4]1=[O:24])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCC1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
30 g (0.092 M) of rac-3-ethyl-5-(o-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 200 ml of absolute acetone, treated with 16 g of powdered potassium carbonate and 8 ml of methyl iodide and the mixture is stirred at room temperature. After 1 hour, a further 4 ml of methyl iodide are added and the mixture is stirred for a further 2.5 hours. The undissolved inorganic salts are filtered off under suction and the solution is concentrated. The residue is treated with water, the mixture is extracted with methylene chloride and the extract is dried with sodium sulphate, filtered and concentrated. After crystallisation from ethyl acetate/petroleum ether, there is obtained rac-3-ethyl-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one which melts at 175°-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[Br:20][C:21](=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:22]=O>>[Br:20][C:21](=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[O:8][C:7](=[O:12])[CH:6]=2)[CH2:15][CH2:16]1
Reactant: O=CC(Br)=Cc1ccccc1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Product: O=c1cc(NC2CCN(CC(Br)=Cc3ccccc3)CC2)c2cc(Cl)ccc2o1
Yield: 25.1 %

Procedure:
According to Procedure A above, 6-chloro-4-(piperidin-4-ylamino)-chromen-2-one and 2-bromo-3-phenyl-propenal (0.046 g, 0.216 mmol) were allowed to react to give the title compound (0.0088 g, 25.1%, mono-TFA salt) as a off-white solid. 1H NMR (400 MHz, MeOH) δ ppm 8.15 (d, J=4, 1H), 7.72 (dd, J=4, 8, 1H), 7.60 (dd, J=4, 8, 1H), 7.39-7.49 (m, 4H), 7.33 (d, J=8, 2H), 5.47 (s, 1H), 4.40 (s, 2H), 3.86-3.97 (m, 1H), 3.64-3.78 (m, 2H), 3.27-3.41 (partially buried m, 2H), 2.30-2.44 (m, 2H), 2.01-2.18 (m, 2H); MS (ESI+Q1MS) m/z 475 [M+H]+
Reaction SMILES: [N:1]([CH:4]([O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH2:5][CH2:6][NH:7]C(=O)C(F)(F)F)=[N+:2]=[N-:3].CO.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:7][CH2:6][CH2:5][CH:4]([N:1]=[N+:2]=[N-:3])[O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(COC(CCNC(=O)C(F)(F)F)N=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(COC(CCN)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 4-[(1-azido-3-trifluoroacetamidopropoxy)methyl]benzoate (220 mg; 0.61 mmol) was added to methanol (2.3 mL) and a solution of potassium carbonate (200 mg; 1.4 mmol) in H2O (1.1 mL). The mixture was vigorously stirred at room temperature for 3 h, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtrated and evaporated. The residue was purified by silica column chromatography (DCM:MeCN 1:1+5% MeOH+1% TEA) to provide methyl 4-[(3-amino-1-azidopropoxy)methyl]benzoate as a liquid in a yield of 110 mg (68%). 1H-NMR (500 MHz, CDCl3): δ=1.78-2.02 ppm (m, 2H), 2.85 ppm (t, J=7.0 Hz, 2H), 3.91 ppm (s, 3H), 4.60 ppm (t, J=6.5 Hz, 1H), 4.62 ppm (d, J=12.5 Hz, 1H), 4.87 ppm (d, J=12.5 Hz, 1H); 13C-NMR (500 MHz, CDCl3): δ=37.79 (in [D6]DMSO this peak splits in two distinct signals with δ=37.92 ppm and 38.93 ppm), 52.21, 70.16, 90.40, 127.55, 129.80, 129.89, 142.17, 166.84 ppm. HRMS [+Scan]; calculated m/z for C12H17N4O3 265.1295; observed mass: 265.1292.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:21][CH:20]([CH:22]([CH3:24])[CH3:23])[CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:18]2[CH2:21][CH:20]([CH:22]([CH3:24])[CH3:23])[CH2:19]2)=[C:4]([C@H:10]([O:17][C:4]([CH3:10])([CH3:5])[CH3:3])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CC(C(C)C)C2)c1Br
Solvent: ClCCl
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(C(C)C)C2)c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 181.8 %

Procedure:
The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of (S)-isopropyl 2-(5-bromo-4-(3-isopropylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (601 mg, 1.5 mmol) and 0.5 mL of 70% HClO4 in DCM (12 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (5-50% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(3-isopropylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate 621 mg (90%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 5.28 (s, 1H), 5.02-4.97 (m, 1H), 4.57 (t, J=8.1 Hz, 1H), 4.40 (t, J=7.7 Hz, 1H), 4.02 (t, J=7.0 Hz, 1H), 3.91 (t, J=7.3 Hz, 1H), 2.44 (s, 3H), 2.33-2.29 (m, 1H), 2.25 (s, 3H), 1.74-1.70 (m, 1H), 1.21 (d, J=6.2 Hz, 3H), 1.17 (d, J=6.2 Hz, 3H), 1.06 (s, 9H), 0.84 (d, J=6.6 Hz, 6H). UPLC (M+H)=457.4.