Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:33][CH3:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:21]>>[CH2:33]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:28][CH2:29][N:30]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:31][CH2:32]1)[CH3:34]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CCCCC1CCNCC1
Product: CCN(CC)CCCCC1CCN(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 62 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[4-(diethylamino)butyl]piperidine in a yield of 62% of theory. Colourless crystals, m.p. 126°-127° C.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8](Cl)=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:27])(=[O:26])[N:17]=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C)C=O>[N:29]([C:8]1[C:9]2[C:14](=[N:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:28])[C:7]=1[C:16]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[S:18](=[O:26])(=[O:27])[N:17]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(Cl)c2cccnc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(N=[N+]=[N-])c2cccnc21
Temperature: 25 °C
Yield: 24.6 %

Procedure:
A solution of the product of Example 165 (0.1 g, 0.24 mmol) and sodium azide (0.037 g, 0.571 mmol) in dimethylformamide (2.5 ml) was stirred at 80° C. for 1.5 hours, allowed to cool to room temperature and concentrated under reduced pressure. The crude residue was purified by a C8 HPLC column eluting with 20% to 80% acetonitrile in water with 1% trifluoroacetic acid to give the title compound (0.025 g, 26% after column purification). MS (ESI−) m/z 422 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 0.94 (t, J=7.35 Hz, 3H), 1.38 (m, 2H), 1.67 (m, 2H), 4.42 (t, J=7.54 Hz, 2H), 7.41 (d, J=7.72 Hz, 1H), 7.46 (dd, J=7.91, 4.60 Hz, 1H), 7.56 (m, 1H), 7.76 (m, 1H), 7.91 (dd, J=8.09, 1.10 Hz, 1H), 8.41 (dd, J=8.09, 1.84 Hz, 1H), 8.84 (dd, J=4.41, 1.84 Hz, 1H), 12.74 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH:16]3[C:23]4[CH:22]=[C:21]([C:24]([O:26]C)=[O:25])[NH:20][C:19]=4[CH2:18][CH2:17]3)[CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Li+].CO>C1COCC1>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH:16]3[C:23]4[CH:22]=[C:21]([C:24]([OH:26])=[O:25])[NH:20][C:19]=4[CH2:18][CH2:17]3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was synthesized from methyl 4-((4′-(trifluoromethyl)biphenyl-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.047 g, 0.12 mmol) and lithium hydroxide (0.052 g, 1.24 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound. 19.4 mg, 43% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.15 (t, J=4.73 Hz, 1H) 2.52-2.62 (m, 3H) 2.78-2.93 (m, 2H) 3.32-3.36 (m, 1H) 6.38 (s, 1H) 7.23-7.27 (m, 1H) 7.36-7.41 (m, 2H) 7.46-7.51 (m, 1H) 7.67-7.77 (m, 4H); LCMS-MS (ESI−) 384.0 (M−H); 19F NMR (376 MHz, METHANOL-d4) δ ppm −64.30 (s, 3F); HPLC (UV=99.3%), (ELSD=100%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C@H:5]([C:14]([OH:16])=O)[CH2:4][CH2:3]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:39][C:40]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:50][NH2:51]>ClCCl>[Cl:39][C:40]1[C:45]([C:46]([F:48])([F:49])[F:47])=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:50][NH:51][C:14](=[O:16])[C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccn1
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCc1cccc(C(F)(F)F)c1Cl)[C@@H]1CCC(=O)N1Cc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
5-oxo-1-(2-pyridinylmethyl)proline (0.220 g, 1 mmol, prepared as described below), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.384 g, 2 mmol), and 1-hydroxybenzotriazole (0.308 g, 2 mmol) were stirred together in dichloromethane (10 ml) at room temperature for 30 minutes. The mixture was then treated with {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (0.314 g, 1.5 mmol) and the mixture was stirred overnight at room temperature. The mixture was concentrated and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was separated and extracted with ethyl acetate and then the combined ethyl acetate fractions were washed with 3 portions of water and then with saturated aqueous sodium chloride solution. Drying over sodium sulphate and concentration gave a solid residue which was purified by mass-directed automated HPLC to give N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-5-oxo-1-(2-pyridinylmethyl)prolinamide (0.263 g) as a buff-coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]3[CH2:13][N:14]([C:17]4[CH:18]=[N:19][C:20](F)=[CH:21][CH:22]=4)[C:15](=[O:16])[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[CH2:24]([N:31]1[CH2:38][CH:37]2[CH:33]([CH2:34][NH:35][CH2:36]2)[CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O>[CH2:24]([N:31]1[CH2:38][CH:37]2[CH2:36][N:35]([C:20]3[N:19]=[CH:18][C:17]([N:14]4[CH2:13][C:11]5[C:10](=[N:9][N:8]([C:5]6[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=6)[CH:12]=5)[C:15]4=[O:16])=[CH:22][CH:21]=3)[CH2:34][CH:33]2[CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Reactant: O=C1c2nn(-c3ccc(Cl)cc3)cc2CN1c1ccc(F)nc1
Solvent: CS(C)=O
Product: O=C1c2nn(-c3ccc(Cl)cc3)cc2CN1c1ccc(N2CC3CN(Cc4ccccc4)CC3C2)nc1
Temperature: 120 °C
Yield: 51.3 %

Procedure:
To a mixture of Example 34A (20 mg, 0.061 mmol) in DMSO (0.8 mL) was added 2-benzyloctahydropyrrolo[3,4-c]pyrrole (58 mg, 0.287 mmol). The resulting mixture was irradiated in microwave reactor at 120° C. for 30 min. The sealed tube was heated at 120° C. for 3 h and allowed to cool down to room temperature. The reaction mixture was subjected to filtration. The solid collected was further washed with MeOH (8 mL) and dried under vacuum to give product (16 mg). The obtained product was diluted with CH2Cl2 (0.8 mL) and TFA (0.2 ml). The resulting mixture was stirred at room temperature for 15 min. The solvent was evaporated to give a crude product which was further purified by preparative HPLC (PHENOMENEX® Luna Axia 5μ C18 30×100 mm; 10 min gradient from 70% A: 30% B to 0% A:100% B (A=90% H2O/10% MeOH+0.1% TFA); (13=90% MeOH/10% H2O+0.1% TFA); detection at 220 nm). The desired fraction was collected and concentrated under SPEEDVAC® to give Example 37 as white solid (9.2 mg, 38%). 1H NMR (CD3OD, 400 MHz) δ 3.02-3.90 (m, 10H), 4.47 (s, 2H), 4.94 (s, 2H), 7.09 (d, J=8.8 Hz, 1H), 7.40-7.53 (m, 7H), 7.60-7.80 (m, 2H), 8.25-8.30 (m, 1H), 8.39 (s, 1H), 8.60 (s, 1H). LCMS, [M+H]+=511.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:19])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=1)[CH3:5].Cl.[H][H]>CO.[Pt]>[CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:5])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[CH:8]=1)[CH3:19]
Reactant: [H][H]
Reactant: COC(=O)C(C)(C)Oc1cccc(-c2cccnc2)c1
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)(C)Oc1cccc(C2CCCNC2)c1
Yield: 88.9 %

Procedure:
2-Methyl-2-(3-pyridin-3-yl-phenoxy)-propionic acid methyl ester (4.07 g, 15.0 mmol) was dissolved in methanol (40 mL) and followed by the addition of 37% HCl (3.8 mL) and 10% Pt/C (0.41 g). The mixture was shaken with hydrogen under 50 psi at 50° C. in a Parr bottle for 2 h, filtered through a pad of Celite, and rinsed with methanol. After solvent removal, the residue was treated with saturated aqueous Na2CO3 (100 mL) and extracted with ethyl acetate (2×100 mL). The organic extract was washed with water, dried over sodium sulfate, and concentrated to give 3.70 g (89%) of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid methyl ester as a yellow oil: 1H NMR (CDCl3) δ 1.57 (br m, 1H), 1.60 (s, 6H), 1.78 (br, 1H), 1.86 (br, 1H), 1.97 (brd, 1H), 2.61 (m, 3H), 3.06–3.13 (m, 2H), 3.76 (s, 3H), 6.61 (dd, 1H), 6.70 (s, 1H), 6.83 (d, 1H), 7.14 (t, 1H); MS m/z (relative intensity) 277 (M+, 2), 218 (6), 176 (100).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1Br
Reaction time: 1.5 h

Procedure:
To a solution of 2-bromo-5-nitrobenzoic acid (1.00 g, 4.06 mmol) in methylene chloride (15 mL) is added oxalyl chloride (1.42 mL, 16.24 mmol) followed by 1 drop DMF. Addition of DMF results in vigorous gas evolution. After 1.5 h, the reaction mixture is concentrated under reduced pressure to give an oil which is used as is without purification.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[Cl:16])[CH3:6]>>[Cl:16][C:10]1[C:9]([CH2:8][O:7][CH2:5][CH3:6])=[CH:14][C:13]([N+:1]([O-:4])=[O:2])=[C:12]([F:15])[CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: CCOCc1ccc(F)cc1Cl
Product: CCOCc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
To a cooled (-40° C.) solution of fuming nitric acid (90%, 25 ml) was added dropwise 2-chloro-4-fluorobenzyl ethyl ether (2.5 g, 0.013 mole) at a rate which maintained the temperature at or below -40° C. Upon completion of addition, the reaction mixture was stirred for 15 minutes at -40° C. The reaction mixture was poured into ice (200 ml) and extracted with methylene chloride (7×40 ml). The extracts were combined, washed with water (2×40 ml), dried (magnesium sulfate) and concentrated under reduced pressure. The residue was passed through a column of silica gel eluting with ethyl acetate:heptane (1:9). Appropriate fractions were combined and concentrated under reduced pressure, yielding 1.07 g of 4-chloro-5-ethoxymethyl-2fluoronitrobenzene. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([Br:20])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([Br:20])[CH:14]=1)[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])=[O:21])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2cc(F)cc(Br)c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(F)cc(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
To a mixture of 4-{[1-(3-bromo-5-fluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.25 g, 6.43 mmol) and ytterbium(III) triflate hydrate (0.40 g, 0.64 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (0.59 mL, 6.43 mmol) and water (0.12 mL, 6.43 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-5-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.33 g, 86%) as a light yellow oil: LC/MS m/e calcd for C20H21BrFNO3 M+: 422.3, observed: 404.3, 406.3.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:42])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41].[CH2:43](I)[CH3:44]>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH2:43][CH3:44])[C:31](=[O:42])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41]
Reactant: COc1ccccc1COC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OCc1ccccc1OC)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 2-methoxybenzyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (66 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of ethyl iodide (84 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (63 mg, yield 93%).
Reaction SMILES: O[C@H:2]([CH2:7][CH2:8][I:9])[C:3]([O:5][CH3:6])=[O:4].N1C(C)=CC=CC=1C.[NH:18]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[NH2:19]>C(Cl)Cl>[I:9][CH2:8][CH2:7][C@H:2]([NH:19][NH:18][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)[C@H](O)CCI
Reactant: NNC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)[C@H](CCI)NNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of methyl (2R)-2-hydroxy-4-iodobutanoate (3.35 g, 13.7 mmol) in DCM (100 mL) under N2 at −70° C. was added 2,6-lutidine (5.67 g, 55 mmol), followed by triflate anhydride (4.07 g, 144.4 mmol) dropwise. Stirring continued at the same temperature for 1 hour. Phenylmethyl hydrazinecarboxylate (2.74 g, 16.5 mmol) was added in one portion, and the reaction mixture was allowed to warm up to room temperature and stirred for 24 hours. The reaction mixture was concentrated, and the crude oil was purified by column chromatography (PE:EA=20:1 to 1:1) to provide phenylmethyl 2-{(1S)-3-iodo-1-[(methyloxy)carbonyl]propyl}hydrazinecarboxylate as yellow oil (3.7 g, 83%). 1H NMR (300 MHz, CDCl3) δ 7.35-7.34 (m, 5H), 6.51 (s, 1H), 5.13 (s, 2H), 4.27 (s, 1H), 3.76-3.70 (m, 4H), 3.42-3.30 (m, 2H), 2.25-2.06 (m, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[C:17]([Cl:38])=[C:18]([CH:33]=[C:34]([C:36]#[N:37])[CH:35]=1)[CH2:19][N:20]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:35]=[C:34]([CH:33]=[C:18]([CH2:19][N:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[C:17]=1[Cl:38])[C:36]#[N:37]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(N)c(Cl)c(CN2CCNCC2)c1
Reaction time: 1 h
Yield: 67.5 %

Procedure:
TFA (1.0 mL) was added to a solution of tert-butyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanobenzyl)piperazine-1-carboxylate (59 mg, 0.13 mmol) in DCM (1.0 mL) at RT. After 1 hr, the solvent was removed and the residue was dissolved in MeOH and applied onto an SCX column. This was washed with MeOH and the product was eluted with 2N NH3 in MeOH to give 3-amino-4-chloro-5-(piperazin-1-ylmethyl)benzonitrile (22 mg) as an oil.
Reaction SMILES: [C:1]([C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[N:6][NH:7][C:8]2=[O:15])#[CH:2].Cl.Br[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>C(NCC)C.O.[Cu]I>[CH3:14][O:13][C:12]1[C:3]([C:1]#[C:2][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:15])[NH:7][N:6]=[CH:5]2
Reactant: Brc1ccncc1
Reactant: C#Cc1c(OC)ccc2c(=O)[nH]ncc12
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Solvent: O
Product: COc1ccc2c(=O)[nH]ncc2c1C#Cc1ccncc1
Temperature: 75 °C
Yield: 86 %

Procedure:
A suspension of 5-ethynyl-6-methoxy-2H-phthalazin-1-one (1.9 g, 9.49 mmoles), prepared as described in example 140, 4-bromopyridine hydrochloride (2.214 g, 11.39 mmoles), bis(triphenylphosphine)PdCl2 (133 mg, 0.1998 mmole) and CuI (36 mg, 0.1898 mmole) in diethylamine (40 ml) was heated at 75° C. for 1 hour, cooled, diluted with water (40 ml) and the solid was filtered after 30 minutes under stirring. The solid was suspended in acetone, stirred for 15 minutes, filtered again and dried in oven at 45° C. under vacuum giving 2.263 g of the title compound (yield: 86%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[C:31]([O:35][C:36](=[O:46])[NH:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1)([CH3:34])([CH3:33])[CH3:32]>C1COCC1>[C:31]([O:35][C:36](=[O:46])[NH:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([NH:45][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12](=[O:13])[C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:15]=4)=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])=[CH:43][CH:44]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CNC(=O)OC(C)(C)C)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 47.8 %

Procedure:
charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added (4-Amino-benzyl)-carbamic acid tert-butyl ester (55.3 mg, 0.249 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture causing a black precipitate to form. The precipitate was vacuum filtered and the filtrate was then concentrated in vacuo and redissolved into ˜3 mL of EtOAc. Hexanes were added causing a yellow precipitate to form. The precipitate was then filtered and washed with ˜1 mL of i-prOH yielding 48% (0.072 g, 0.119 mmol) of the title compound.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[NH:14])[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH:15]([C:27](OCC)=[O:28])([C:22](OCC)=[O:23])[CH2:16][C:17]([O:19][CH2:20]C)=[O:18].C[O-].[Na+].Cl>O.CO>[OH:23][C:22]1[C:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:27]([OH:28])[N:13]=[C:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)[N:14]=1
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)Cc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)Cc1c(O)nc(Cc2ccc([N+](=O)[O-])cc2)nc1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 250 mL round bottom flask was charged with 2-(4-nitrophenyl)ethanimidamide hydrochloride (approximately 6.47 g, 30.0 mmol, 48% purity), triethyl ethane-1,1,2-tricarboxylate (7.60 mL, 33.0 mmol) and methanol (43 mL). To this solution was added a 25% sodium methoxide solution in methanol (24.0 mL, 105.2 mmol) immediately resulting in a dark purple thick suspension. After stirring for three hours under reflux the dark purple mixture was cooled to 0° C. using an ice bath and carefully treated with 30 mL water. This mixture was slowly treated with 35 mL 6N hydrochloric acid giving a pale green suspension. The suspension was stirred for additional 30 minutes, filtered and the obtained fawn solid was washed with 100 mL water. The product was dried in a desiccator under vacuum for two days. The crude product was used without purification in the next step.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](ON)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.15 g, 0.54 mmol) in dry DCM (20 mL) were added tert-butyl (3R)-3-(aminooxy)pyrrolidine-1-carboxylate 2 (0.17 g, 0.81 mmol, J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.11 g, 0.81 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16 g, 0.81 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give compound tert-butyl (3R)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate 3 (0.23 g, 93%) as a clear thick oil.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:14]=[N:15][CH:16]=2)[CH:2]=1.[C:21]([N:29]=C=O)(=[O:28])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[OH:20][C:17]([C:13]1[CH:12]=[C:11]([C:3]2[CH:4]=[C:5]3[C:10](=[N:1][CH:2]=2)[N:9]([C:21]([NH2:29])=[O:28])[CH2:8][CH2:7][CH2:6]3)[CH:16]=[N:15][CH:14]=1)([CH3:18])[CH3:19]
Reactant: CC(C)(O)c1cncc(-c2cnc3c(c2)CCCN3)c1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(O)c1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Temperature: 50 °C
Yield: 32 %

Procedure:
2-[5-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-propan-2-ol (33 mg, 0.12 mmol) and benzoyl isocyanate (40 mg, 0.25 mmol) are mixed in 1.0 mL of DCM and the mixture is heated at 50° C. for 16 hrs. Then the solvent is removed and the residue is dissolved in 1.0 mL of EtOH. K2CO3 (29 mg, 0.21 mmol) is added and the mixture is heated at 80° C. for 2 hrs, cooled down to room temperature for 16 hrs and heated at 80° C. again for another 3 hrs. Then the solvent is removed and the residue is partitioned between water (15 mL) and EtOAc (25 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. The crude is purified by flash column chromatography to give 12 mg of the titled product.