Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([CH3:36])([CH2:34][CH3:35])[CH2:8][C:9]1[N:10]=[C:11]([CH3:33])[N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1.[F:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2[CH:55]=[CH:54][C:47]([C:48](N(OC)C)=[O:49])=[CH:46][CH:45]=2)=[N:42][CH:43]=1>O1CCCC1>[CH3:6][C:7]([CH3:36])([CH2:34][CH3:35])[CH2:8][C:9]1[N:10]=[C:11]([CH2:33][C:48]([C:47]2[CH:46]=[CH:45][C:44]([C:41]3[CH:40]=[CH:39][C:38]([F:37])=[CH:43][N:42]=3)=[CH:55][CH:54]=2)=[O:49])[N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1
Reactant: CON(C)C(=O)c1ccc(-c2ccc(F)cn2)cc1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(=O)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
n-Butyllithium (2.5 M in hexanes) (0.53 mL, 1.32 mmol) was added to a solution of 4-(2,2-dimethylbutyl)-2-methyl-1-trityl-1H-imidazole (360 mg, 0.88 mmol) in tetrahydrofuran (15 mL) at −78° C. dropwise. After stirring at −78° C. for 40 min, 4-(5-fluoropyridin-2-yl)-N-methoxy-N-methylbenzamide (340 mg, 1.32 mmol) in tetrahydrofuran (5 mL) was added dropwise. After warming slowly to ambient temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-20% ethyl acetate/hexane afforded 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanone contaminated with an unidentified byproduct. This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][C:6]3([O:13][CH2:14][CH2:15][OH:16])[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([CH2:17][N:18]4[C:22]([CH3:23])=[C:21]([I:24])[CH:20]=[N:19]4)([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl.C(OCC)(=O)C>[CH3:32][S:33]([O:16][CH2:15][CH2:14][O:13][C:6]12[CH2:12][C:2]3([CH3:1])[CH2:9][C:8]([CH3:11])([CH2:10][C:4]([CH2:17][N:18]4[C:22]([CH3:23])=[C:21]([I:24])[CH:20]=[N:19]4)([CH2:3]3)[CH2:5]1)[CH2:7]2)(=[O:35])=[O:34]
Reactant: Cc1c(I)cnn1CC12CC3(C)CC(C)(C1)CC(OCCO)(C3)C2
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(I)cnn1CC12CC3(C)CC(C)(C1)CC(OCCOS(C)(=O)=O)(C3)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cold (0° C.) solution of EXAMPLE 82C (2.1 g) in methylene chloride (30 mL) was added triethylamine (1.42 g) followed by methanesulfonyl chloride (0.542 g). The mixture was stirred at room temperature for 1.5 hours and then was diluted with ethyl acetate (300 mL). The layers were separated, and the organic layer was washed with water (60 mL) and brine (60 mL), dried with Na2SO4, filtered and concentrated to give the title compound, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([N:17]([CH2:19][CH2:20][O:21][CH3:22])[CH3:18])=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[N+:23]([O-])=O>[Pd].C(OCC)(=O)C.CO>[CH3:22][O:21][CH2:20][CH2:19][N:17]([CH3:18])[C:15]1[CH:14]=[CH:13][C:11]2[NH:12][C:8]([C:5]3[CH:4]=[C:3]([NH2:23])[C:2]([NH2:1])=[CH:7][CH:6]=3)=[N:9][C:10]=2[CH:16]=1
Reactant: COCCN(C)c1ccc2[nH]c(-c3ccc(N)c([N+](=O)[O-])c3)nc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCN(C)c1ccc2[nH]c(-c3ccc(N)c(N)c3)nc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [2-(4-amino-3-nitro-phenyl)-1H-benzoimidazol-5-yl]-(2-methoxy-ethyl)-methyl-amine (0.65 g, 1.9 mmol) in 4:1 ethyl acetate/methanol (50 ml) under nitrogen, was added 5% palladium on carbon (100 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through celite, washed with 1:1 ethyl acetate/methanol (10 mL) and the combined filtrate and washings were concentrated to give the crude 4-{5-[(2-methoxy-ethyl)-methyl-amino]-1H-benzoimidazol-2-yl}-benzene-1,2-diamine as a thick oil that was used in the next step without any purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10](Cl)=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].CN(C)[C@@H]1CCN(CC2C=CC(C(O)=O)=CC=2)C1.[O:40]1[CH2:45][CH2:44][N:43]([CH:46]2[CH2:50][CH2:49][N:48]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=3)[CH2:47]2)[CH2:42][CH2:41]1>>[O:40]1[CH2:45][CH2:44][N:43]([CH:46]2[CH2:50][CH2:49][N:48]([C:51]3[CH:59]=[CH:58][C:54]([C:55]([NH:1][C:2]4[CH:7]=[C:6]([C:8]5[S:9][CH:10]=[CH:11][CH:12]=5)[CH:5]=[CH:4][C:3]=4[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:56])=[CH:53][CH:52]=3)[CH2:47]2)[CH2:42][CH2:41]1
Reactant: O=C(O)c1ccc(N2CCC(N3CCOCC3)C2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Cl)s2)cc1N
Agent: CN(C)[C@@H]1CCN(Cc2ccc(C(=O)O)cc2)C1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(N2CCC(N3CCOCC3)C2)cc1
Yield: 40 %

Procedure:
Following the same procedure as described in Example 1, step 6 (scheme 1), but substituting compound 4 for compound 168 and compound 7 for compound 269, title compound 270 was obtained in 40% yield.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=5[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:37])[CH2:35][CH2:34]1
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@@H](N)CC3)c[nH]c12
Reactant: O=C(Cl)C1CC1
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@@H](NC(=O)C4CC4)CC3)c[nH]c12

Procedure:
Starting from cis-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A183) and cyclopropanecarbonyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O.[CH3:24]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CO
Reactant: O=C(O)CCc1conc1-c1ccc(F)c(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1conc1-c1ccc(F)c(Cl)c1
Yield: 96 %

Procedure:
A mixture of 3-[3-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionic acid (4.34 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[3-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionate (4.39 g, yield 96%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 39–40° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([NH2:26])[CH2:25][O:24][CH2:23]1>>[CH3:21][C:22]1([NH:26][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:25][O:24][CH2:23]1
Reactant: CC1(N)COC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CC1(NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)COC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (3-methyloxetan-3-yl)-amine (CAN 874473-14-0) as starting materials.
Reaction SMILES: [Na].C[CH2:3][O:4][C:5](/[CH:7]=[C:8](/[CH2:10]P(OCC)(OCC)=O)\[CH3:9])=[O:6].[CH3:19][CH:20]([N:22]1[C:31]2[C:26](=[CH:27][C:28](/[C:32](/[CH3:36])=[CH:33]/[CH:34]=O)=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1)[CH3:21].[Cl-].[NH4+]>CO>[CH3:21][CH:20]([N:22]1[C:31]2[C:26](=[CH:27][C:28](/[C:32](/[CH3:36])=[CH:33]/[CH:34]=[CH:10]/[C:8](/[CH3:9])=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1)[CH3:19]
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: C/C(=C\C=O)c1ccc2c(c1)CCCN2C(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CO
Product: COC(=O)/C=C(C)/C=C/C=C(\C)c1ccc2c(c1)CCCN2C(C)C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
56 mg (2.46 mmol) of metallic sodium was added to methanol to prepare a meethanolic solution or sodium meethoxide. This solution was concentrated in a vacuum and suspended in N,N-dimethylformamide, followed by the addition of 560 mg (2.14 mmol) of triethyl 3-methyl-4-phosphonocrotonate under cooling with ice. After 30 minutes, 400 mg (1.64 mmol) of (E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-butenal was added to the mixture obtained above. The mixture thus obtained was stirred for one hour, followed by the addition of an aqueous solution of ammonium chloride. The obtained mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated in a vacuum. The obtained residue was purified by silica gel column chromatography (15% ethyl acetate/n-hexane) to give 330 mg of the title compound as a reddish-brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[K+].C(OCC)(=O)C>CS(C)=O.O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Oc1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1cccc(Oc2ccccc2)n1
Temperature: 160 °C
Reaction time: 7 h
Yield: 93 %

Procedure:
To a solution of 2,6dibromopyridine (20 g, 84.4 mmol) and phenol (7.94 g, 84.4 mmol) in dimethylsulfoxide (200 mL) was added potassium tert-butoxide (9.47 g, 84.4 mmol), and the solution was stirred at 160° C. for 7 hours. The reaction solution was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and 2-bromo-6-phenoxy-pyridine (19.6, 93%) was obtained as a yellow solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH:26]12[NH:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][NH:28][C:27]2=[O:34].C(N(CC)CC)C>CN1C(=O)CCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:33]5[CH:30]6[CH2:31][CH2:32][CH:26]5[C:27](=[O:34])[NH:28][CH2:29]6)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: O=C1NCC2CCC1N2
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3C4CCC3C(=O)NC4)cc1OCC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 29.2 %

Procedure:
To a suspension of 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 (137 mg, 0.44 mmol) in NMP (1.2 mL) was added sodium hydride (60% in mineral oil, 21 mg, 0.53 mmol). The reaction mixture was stirred at RT for 45 min, then at 45° C. for 45 min then cooled to RT. Phenyl trifluorosulphonimide (189 mg, 0.53 mmol) was added and the reaction stirred at RT for 1 h. 3,8-diaza-bicyclo[3.2.1]octan-2-one (69 mg, 0.48 mmol) and triethylamine (77 μL, 0.44 mmol) were added and the reaction mixture heated at 100° C. for 72 h then 120° C. for 7 h. The reaction mixture was cooled to RT, quenched with water and the resulting solid filtered and dried in vacuo. The resultant solid was loaded onto an Isolute SCX-2 cartridge, washed with methanol and eluted with 2M ammonia in methanol. Basic fractions were combined and concentrated in vacuo, the resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 466 (54 mg, 29%). LCMS: RT=2.33 min, [M+H]+=421. 1H NMR 300 MHz (DMSO-d6) δ: 9.13 (1 H, s), 7.88 (2 H, d, J=8.29 Hz), 7.19 (1 H, br, s), 6.42 (1 H, s), 5.95 (1 H, m), 4.53 (4 H, d, J=10.45 Hz), 4.50 (1 H, m), 3.49 (1 H, m), 3.17 (1 H, d, J=5.21 Hz), 2.98 (1 H, m), 2.05-2.20 (2 H, m), 1.99 (1 H, m), 1.95-1.98 (1 H, m), 1.48 (6 H, dd, J=6.57, 2.41 Hz)
Reaction SMILES: [CH3:1][C:2]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])([O:4][N:5]1C(=O)C2=CC=CC=C2C1=O)[CH3:3].O.NN>C(Cl)Cl>[CH3:3][C:2]([O:4][NH2:5])([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])[CH3:1]
Reactant: CC(C)(ON1C(=O)c2ccccc2C1=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: O
Solvent: ClCCl
Product: CC(C)(ON)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
In 80 ml of methylene chloride is dissolved 7.68 g of N-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxy]phthalimide and under ice-cooling and stirring 0.97 ml of hydrazine hydrate is added. The mixture is stirred at room temperature for 2 hours, after which 0.97 ml of hydrazine hydrate is further added. The mixture is stirred for 3 hours and the resultant crystalline precipitate is separated by filtration and washed with methylene chloride. The filtrate and washings are combined and further washed with diluted aqueous ammonia and water in this order, and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is chromatographed on a silica gel column [silica gel: 300 g; eluent: ethyl acetate-hexane (1:1)] to give 4.58 g of O-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyl]hydroxylamine as a yellow oil. This product solidifies on cooling.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH2:10](N(CC)CC)C.COC(Cl)Cl>O1CCCC1>[CH3:9][C:3]1[C:2]2[N:1]=[CH:10][NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCN(CC)CC
Reactant: Cc1cccc(N)c1N
Agent: COC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cccc2[nH]cnc12
Temperature: 0 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
2,3 Diaminotoluene (675 mg, 5.53 mmol) was dissolved in 10 mL of dry tetrahydrofuran and triethylamine (0.77 mL, 5.53 mmol) was added. The mixture was cooled to 0° C. and 1,1-dichloromethyl methyl ether (0.50 mL, 5.53 mmol) was added and the reaction was allowed to warm to room temperature. After 20 hours, the reaction was quenched with sodium bicarbonate. The aqueous phase was extracted with ethyl acetate, dried over magnesium sulfate, filtered and the solvent removed to yield 730 mg (100%) of a brown solid.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.C([N:32]1[C:36]2=[N:37][CH:38]=[CH:39][C:40]([C:41]3[CH:42]=[N:43][N:44]([CH2:46][C:47]#[N:48])[CH:45]=3)=[C:35]2[CH:34]=[N:33]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ICC>C1COCC1>[NH:32]1[C:36]2=[N:37][CH:38]=[CH:39][C:40]([C:41]3[CH:42]=[N:43][N:44]([CH:46]([CH2:1][CH3:2])[C:47]#[N:48])[CH:45]=3)=[C:35]2[CH:34]=[N:33]1
Reactant: N#CCn1cc(-c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(C#N)n1cc(-c2ccnc3[nH]ncc23)cn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 57.2 %

Procedure:
A solution of diisopropylamine (229.8 mg, 318.3 μL, 2.271 mmol) in THF (10 mL) at 0° C. was treated with butyllithium (698.8 μL of 2.5 M, 1.747 mmol) and then allowed to cool to −78° C. This was then added dropwise to a solution of 2-[4-(1-tritylpyrazolo[5,4-b]pyridin-4-yl)pyrazol-1-yl]acetonitrile (815 mg, 1.747 mmol) over a period of 20 minutes. After a further 30 minutes the reaction was treated with iodoethane (544.9 mg, 279.4 μL, 3.494 mmol) at −78° C. and the ice bath removed. The reaction was allowed to stir for 1.5 hours and then treated with brine/EtOAc and the two layers separated. The organics were dried (MgSO4), filtered and concentrated. The resultant residue was taken up in DCM (12 mL) and treated with triethylsilane (4 mL) and TFA (0.5 mL) and allowed to stir at RT for 2 hours. The reaction was concentrated in vacuo and purified by column chromatography (10% MeOH/DCM) to give the product as a pure white solid (252 mg, 57% Yield). 1H NMR (DMSO, 400 MHz) δ 0.95 (3H, t), 2.23-2.28 (2H, m), 5.79 (1H, t), 7.46 (1H, d), 8.46 (1H, s), 8.48 (1H, d), 8.52 (1H, d), 8.83 (1H, s), 13.73 (1H, br s); MS (ES+) 253.09
Reaction SMILES: [N:1]1[C:10]2[C:9](=[O:11])[CH:8]=[CH:7][C:6](=[O:12])[C:5]=2[N:4]=[CH:3][CH:2]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1>[C:14]1([CH2:13][N:20]2[CH2:21][CH2:22][N:23]([C:8]3[C:9](=[O:11])[C:10]4[N:1]=[CH:2][CH:3]=[N:4][C:5]=4[C:6](=[O:12])[CH:7]=3)[CH2:24][CH2:25]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1C=CC(=O)c2nccnc21
Solvent: C1COCCO1
Product: O=C1C=C(N2CCN(Cc3ccccc3)CC2)C(=O)c2nccnc21
Reaction time: 3 h
Yield: 32.9 %

Procedure:
A mixture of 160 mg of 5,8-quinoxalinedione and 352 mg of 1-benzylpiperazine in 10 ml of dioxane was stirred or 3 hours. The solvent was then removed and the residue triturated with ether. This solid was collected, washed with ether and dried, giving 110 mg of the desired product, mp 165°-168° C. (dec.).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([O:19][CH2:20][CH3:21])=[N:9]1)C1C=CC=CC=1.C(O)=O>[C].[Pd].C(O)C>[CH2:20]([O:19][C:10]1[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][NH:8][N:9]=1)[CH3:21]
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCC
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: CCOC(=O)Cc1c[nH]nc1OCC
Yield: 54.1 %

Procedure:
A mixture of ethyl 1-benzyl-3-ethoxy-1H-pyrazol-4-ylacetate (7.50 g), 5% palladium-carbon (15.0 g), formic acid (50 ml) and ethanol (100 ml) was refluxed for 1 hour. After cooling, the palladium-carbon was removed by filtration, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, which was washed with saturated aqueous sodium bicarbonate solution, and with a saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1H-pyrazol-4-ylacetate (2.79 g, yield 54%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:16])[NH:4][C:5](=[O:15])[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1>CC#N.CCOC(C)=O>[CH:25]1([CH2:24][N:4]2[C:3](=[O:16])[C:2]([CH3:1])=[CH:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[C:5]2=[O:15])[CH2:27][CH2:26]1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c(=O)[nH]c1=O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cn(C(=O)OC(C)(C)C)c(=O)n(CC2CC2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
Tert-butyl 5-methyl-2,4-dioxo-pyrimidine-1-carboxylate (0.10 g, 0.44 mmol) was dissolved in dry MeCN (2.2 mL) and cesium carbonate was added (0.22 g, 0.66 mmol), followed by (bromomethyl)cyclopropane (0.13 mL, 1.33 mmol). The reaction mixture was stirred under nitrogen atmosphere at room temperature for 18 hrs. The reaction was then diluted with EtOAc and saturated aqueous NH4CI solution was added. The aqueous layer was extracted with EtOAc (3×15 mL), the combined organic phases were washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude was purified by column chromatography using a Teledyne ISCO apparatus (petroleum ether:EtOAc 80:20) to afford the title compound (0.09 g, 72%) as white solid. 1H NMR (400 MHz, CDCl3) δ 0.38-0.43 (m, 2H), 0.43-0.50 (m, 2H), 1.21-1.32 (m, 1H), 1.61 (s, 9H), 1.97 (s, 3H), 3.84 (d, J=7.2 Hz, 2H), 7.64 (s, 1H). MS (ESI) m/z: 303 [M-Na]−.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@@H:15]([CH3:29])[CH2:16][O:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([N+:25]([O-:27])=[O:26])[C:19]=1F)(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[F:24][C:23]1[C:18]2[O:17][CH2:16][C@H:15]([CH3:29])[NH:14][C:19]=2[C:20]([N+:25]([O-:27])=[O:26])=[CH:21][CH:22]=1
Reactant: C[C@@H](COc1c(F)ccc([N+](=O)[O-])c1F)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@H]1COc2c(F)ccc([N+](=O)[O-])c2N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
TFA (3 mL) was added to a solution of [(S)-2-(2,6-difluoro-3-nitrophenoxy)-1-methylethyl]carbamic acid tert-butyl ester (340 mg, 1.02 mmol) in DCM (15 mL) and the mixture was stirred for 90 min at rt. PhMe (25 mL) was added and the solution was concentrated in vacuo. The resultant residue was taken up in MeCN (7 mL); aqueous 2M Na2CO3 (7 mL) was added and the mixture was stirred vigorously for a further 90 min at rt. EtOAc (25 mL) and brine (25 mL) were added and the phases were separated. The aqueous was extracted with EtOAc (2×25 mL), and the combined organics were dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Si—PPC, gradient 0-20% EtOAc in cyclohexane) to afford the title compound as a bright yellow solid (183 mg, 84%). 1H NMR (CDCl3, 300 MHz): δ 7.85 (1H, br s), 7.78 (1H, dd, J=9.8, 5.5 Hz), 6.45 (1H, app. t, J=9.8 Hz), 4.36-4.28 (1H, m), 3.84-3.77 (2H, m), 1.35 (3H, d, J=6.2 Hz)
Reaction SMILES: CS([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([C:15]2[C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[O:14])=[CH:7][CH:6]=1)(=O)=O.[CH3:32][O:33][C:34](=[O:38])[C:35](Cl)=O>C1COCC1>[CH3:32][O:33][C:34]([C:35]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:16]2[C:15]([C:13](=[O:14])[C:12]=1[CH2:11][C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1)=[CH:20][CH:19]=[C:18]([CH3:21])[N:17]=2)=[O:38]
Reactant: COC(=O)C(=O)Cl
Reactant: Cc1ccc(C(=O)CCc2ccc(S(C)(=O)=O)cc2)c(Nc2cccc([N+](=O)[O-])c2)n1
Solvent: C1CCOC1
Product: COC(=O)c1c(Cc2ccccc2)c(=O)c2ccc(C)nc2n1-c1cccc([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
3-(4-Methanesulfonyl-phenyl)-1-[6-methyl-2-(3-nitrophenylamino)-pyridin-3-yl]-propan-1-one (0.1 g) was dissolved in THF (5 mL). Chloro-oxo-acetic acid methyl ester (0.1 mL) was added, and the mixture heated by microwave at 80° C. for 1 h. The product was concentrated, the residue taken up in MeOH (5 mL), K2CO3 (0.1 g) added, and the mixture heated at 50° C. for 15 min. The product was cooled and concentrated, and purified by prep TLC (50% EtOAc/hexane) to provide 3-benzyl-7-methyl-1-(3-nitrophenyl)-4-oxo-1,4-dihydro[1,8]-naphthyridine-2-carboxylic acid methyl ester (Compound 104, ˜20 mg). M+H=508.