Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12.Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:3]=12.[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: Ic1ccnc2cn[nH]c12
Reactant: COc1ccc(CCl)cc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc3nccc(I)c3n2)cc1
Product: COc1ccc(Cn2ncc3nccc(I)c32)cc1
Temperature: 25 °C

Procedure:
To 7-iodo-1H-pyrazolo[4,3-b]pyridine (500 mg, 2.041 mmol) in DMF (10 mL) at 0° C. was added 1-(chloromethyl)-4-methoxybenzene (0.292 mL, 2.143 mmol) and the reaction was allowed to warm to room temperature over 1 hour. The reaction mixture was then quenched with saturated ammonium chloride solution and extracted with ethyl acetate (50 mL×2). The organic layers were dried over sodium sulfate and concentrated to give a residue which was loaded onto silica and purified using a 0-77% gradient of ethyl acetate in hexanes to give 7-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine and 7-iodo-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridine which was used immediately. MS [M+H] found 366.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C([Li])CCC.[N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[N:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CO>O1CCCC1>[CH3:1][C:2]1([CH3:11])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH:9]=2)[CH:4]=[CH:3]1.[CH3:1][C:2]1([CH3:11])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CC1(C)CCc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(c1)C(C)(C)C=C2
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(c1)C(C)(C)CC2
Temperature: 25 °C
Yield: 37.2 %

Procedure:
6-Bromo-1 μl-dimethyl-indan (prepared by using a well-known method: patent application WO2005066115) 4a (4.32 g, 19.27 mmol) was dissolved in 40 mL of tetrahydrofuran and then butyllithium (15.67 mL, 1.6 M, 25.05 mmol) was added dropwise at −78° C. After the reaction mixture was reacted for 40 minutes, a solution of di-tert-butyl azodicarboxylate (5.32 g, 23.12 mmol) in 30 mL of tetrahydrofuran was then added. The reaction mixture was reacted for another 3 hours at −78° C. The reaction mixture was added with 5 mL of methanol, then warmed up to room temperature and filtered by silica gel. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound di-tert-butyl 1-(3,3-dimethyl-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 4b (2.70 g, yield 37.2%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[C:25](Cl)=[O:26].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[CH3:32][O:31][C:29]1[CH:28]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[CH:30]=1)[C:25]([C:10]1[C:11]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=2[S:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:26]
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2cc(OC)cc(OC)c2)cc1
Reaction time: 17 h
Yield: 48 %

Procedure:
To a well-stirred solution of 2-(4′-methoxyphenyl)-6-methoxybenzo[b]thiophene (0.615 g, 2.27 mmol) and 3,5-dimethoxybenzoyl chloride (1.37 g, 6.83 mmol) in CH2Cl2 (45 mL) was added AlCl3 (1.21 g, 9.09 mmol) portion-wise over a 15 minute period. After 17 hours, water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed with brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 60:40 EtOAc/hexane) afforded the title compound (0.475 g, 1.09 mmol, 48%) as an off-white solid. Recrystallization (hexane/ethanol) afforded a highly pure, crystalline sample with mp 114-120° C.: 1H-NMR (CDCl3, 360 Mhz): δ=7.59 (d, J=8.9 Hz, 1H, ArH), 7.32 (d, J=8.5 Hz, 2H, ArH), 7.32 (d, J=2.4 Hz, 1H, ArH), 6.98 (dd, J=9.0, 2.4 Hz, 1H, ArH), 6.94 (d, J=2.1 Hz, 2H, ArH), 6.76 (d, J=8.7 Hz, 2H, ArH), 6.52 (t, J=2.4 Hz, 1H, ArH), 3.89 (s, 3H, —OCH3), 3.76 (s, 3H, —OCH3), 3.71 (s, 6H, —OCH3); 13C-NMR (CDCl3, 90 Mhz): δ=194.0, 160.5, 159.8, 157.7, 143.9, 140.0, 139.3, 133.8, 130.3, 130.1, 126.0, 124.1, 114.9, 114.0, 107.6, 106.1, 104.4, 55.6, 55.5, 55.2. HRMS (EI) M+ calcd for C25H22O5S 434.1188, found 434.1245. Anal. Calcd. for C25H22O5S: C, 69.11; H, 5.10; S, 7.38. Found: C, 69.00; H, 5.16; S, 7.34.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14](O)[CH2:13][C@H:12]1[C:17]([O:19][CH3:20])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Na+].C(N(/C(/F)=C(\F)/C(F)(F)[F:31])CC)C.C(N(C(F)(F)C(F)C(F)(F)F)CC)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:31])[CH2:13][C@H:12]1[C:17]([O:19][CH3:20])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CCN(CC)/C(F)=C(\F)C(F)(F)F
Agent: CCN(CC)C(F)(F)C(F)C(F)(F)F
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
Methyl(2S,4R)-1-benzyloxycarbonyl-4-hydroxypyrrolidine-2-carboxylate (306 mg, 0.00108 mol) and sodium fluoride (55 mg, 0.00131 mol) were suspended in dichloromethane (1.8 mL), followed by addition of Ishikawa reagent (293 mg, 0.00131 mol) under ice cooling. The reaction mixture was slowly warmed to room temperature and then stirred for 20 hours. After the reaction, the reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate (5 mL) and then separated into organic and aqueous layers. The aqueous layer was extracted with ethyl acetate. This extracted solution was combined with the organic layer obtained above, washed sequentially with 10% aqueous potassium bisulfate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. After drying, the solvent and the decomposition product of Ishikawa reagent (N,N-diethyl-2,3,3,3-tetrafluoropropionamide) were distilled off under reduced pressure, and the residue was applied to silica gel column chromatography (developing solvent; hexane:ethyl acetate=5:1 to 0:1) to give the titled compound (227 mg, colorless oil).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(C(O)=O)[C:7]2([CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].C1C=CC(P([N:28]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[ClH:38].O1CCOCC1>CC(O)(C)C>[ClH:38].[CH3:1][O:2][C:3]([C:5]1([NH2:28])[C:7]2([CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(=O)O)CC12CCC2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: COC(=O)C1(N)CC12CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a mixture of spiro[2,3]hexane-1,1-dicarboxylic acid methyl ester (660 mg, 3.58 mmol) in 3 mL of anhydrous t-BuOH was added 1.08 g (3.92 mmol) of DPPA and 440 mg (4.35 mmol) of Et3N. The mixture was heated at reflux for 21 h and then partitioned between H2O and ether. The ether phase was dried over magnesium sulfate, filtered and concentrated in vacuo to yield an oil. To this oil was added 3 mL of a 4 M HCl/dioxane solution. This acidic solution was stirred at rt for 2 h and then concentrated in vacuo. The residue was triturated with ether to give 400 mg (58%) of desired product as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 8.96 (br s, 3H), 3.71 (s, 3H), 2.41 (m, 1H), 2.12 (m, 4H), 1.93 (m, 1H), 1.56 (q, 2 H, J=8 Hz). LC-MS of free amine: MS m/z 156 (M++1).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[NH:13]([C:20]([C:23]1[N:24]([CH3:35])[C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[N:26][N:27]=1)([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH2:8]([NH:10][C:11](=[O:12])[O:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[N:24]([CH3:35])[C:23]([C:20]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([CH3:22])[CH3:21])=[N:27][N:26]=2)=[CH:29][CH:30]=1)[CH3:9]
Reactant: Cn1c(-c2ccc(O)cc2)nnc1C(C)(C)Nc1ccccc1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Oc1ccc(-c2nnc(C(C)(C)Nc3ccccc3)n2C)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Triethylamine and ethyl isocyanate were added to a chloroform solution (3 ml) of 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl}phenol (20 mg), followed by stirring at 60° C. for 3 hours. After concentration, a small amount of ethyl acetate was added to the residue and the resulting crystalline powder was filtered to obtain 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl}phenyl ethylcarbamate.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](Cl)=[N:12][C:11]=2[N:10]=[C:9]1[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:33].[Na+]>O1CCOCC1>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:33])[NH:12][C:11]=2[N:10]=[C:9]1[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC1=Nc2nc(C3CCCC3)n(Cc3ccccc3)c2C2=N[C@H](Cc3ccccc3)CN12
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1Nc2nc(C3CCCC3)n(Cc3ccccc3)c2C2=N[C@H](Cc3ccccc3)CN12
Temperature: 70 °C
Yield: 90 %

Procedure:
Compound 66 (1.87 g, 4.21 mmol) obtained in Example 66 was dissolved in 1,4-dioxane (30 mL), to the solution was added 2 mol/L aqueous sodium hydroxide (15 mL), and the mixture was stirred with heating at 70° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and then the residue was neutralized by addition of concentrated hydrochloric acid. The deposited crystals were collected by filtration, washed with water and dried to obtain (R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77a, 1.61 g, 90%). Compound 77a (500 mg, 1.08 mmol) was dissolved in N,N-dimethylformamide (5 mL), to the solution were added potassium carbonate (192 mg, 1.41 mmol, 1.2 equivalents) and bromoacetic acid methyl ester (140 μL, 1.41 mmol, 1.2 equivalents), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water was added to the concentrate, the mixture was extracted with chloroform, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=90:10) to obtain (R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77b, 400 mg, 69%). From Compound 77b (850 mg, 1.71 mmol), (R)-8-benzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77c, 220 mg, 29%) was obtained in a manner similar to the method by which Compound 40 was obtained from Adduct 40a in Example 40. Compound 77c (200 mg, 0.49 mmol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL) and water (1 mL), to the solution was added lithium hydroxide hydrate (0.04 g, 0.98 mmol), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was adjusted to pH 3 with 1 mol/L hydrochloric acid, and the resulting solid was washed with ethanol and collected by filtration to obtain the title compound (180 mg, 93%).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][NH:5][C:6]([C:8]1[C:13]([OH:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:10][N:9]=1)=[O:7].[OH-].[Na+].Cl>C1COCC1>[Cl:21][C:17]1[CH:16]=[C:15]([C:11]2[CH:12]=[C:13]([OH:14])[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:22])=[O:2])=[O:7])=[N:9][CH:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CNC(=O)c1ncc(-c2cccc(Cl)c2)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ncc(-c2cccc(Cl)c2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of {[5-(3-chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester, 6, (0.163 g, 0.509 mmol) in THF (5 mL) is added 1M NaOH (1.5 ml, 1.27 mmol) and the reaction mixture stirred at room temperature for 1 hour. The solution is acidified using 1M HCl (3 mL), the solvent removed under reduced pressure and the resulting solid suspended in CHCl3:iso-propanol (1:1), filtered and the filtrate dried (MgSO4), filtered and re-concentrated under reduced pressure. The crude material is triturated with a small amount of MeOH to afford 0.10 g (64% yield) of the desired product as a colorless solid. 1H NMR (400 MHz, MeOD) δppm 8.31 (1H, d, J=1.8 Hz), 7.47 (2 H, d, J=1.8 Hz), 7.30-7.65 (4H, m), 4.07 (2H, s). HPLC-MS: m/z 307 [M+H]+.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[Cl-:47].[OH2:48]>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:47])=[CH:12][CH:11]=3)=[O:48])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O
Reactant: [Cl-]
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.210 g, 0.35 mmol) in pyridine (2 mL) was added 4-chliorobenzoyl chloride (0.051 mL, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.090 g, 62% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 14.20 (br s, 1H), 13.45 (br s, 1H), 10.54 (s, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 8.10 (d, 1H), 8.04 (d, 2H), 7.93 (d, 1H), 7.76 (d, 1H), 7.71 (d, 1H), 7.64 (d, 2H), 7.56 (t, 1H); ES-MS (m/z) 415 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:10][C:9](=[O:20])[C:8]=3[CH2:7][CH2:6][N:5]2[C:21]=1[CH3:22].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[OH-].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:10][C:9](=[O:20])[C:8]=3[CH:7]=[CH:6][N:5]2[C:21]=1[CH3:22]
Reactant: Cc1nc2n(c1C)CCC1=C2N[C@H](c2ccccc2)CC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nc2c3c(ccn2c1C)C(=O)C[C@@H](c1ccccc1)N3
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
63.5 g (0.22 mol) of (9S)-2,3-dimethyl-9-phenyl-5,6,7,8,9,10-hexahydroimidazo[1,2-h][1,7]naphthyridin-7-one are dissolved in 250 ml of toluene and 250 ml of tetrahydrofuran, and cooled to 0° C. 59 g (0.26 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are introduced in portions of 10 g over a period of 1 h with mechanical stirring. The reaction mixture is stirred at room temperature for 16 h. 1.2 l of 0.5 N sodium hydroxide solution and 1 l of ethyl acetate are then added dropwise. The organic phase is removed and washed with water. The aqueous phase is reextracted with ethyl acetate, and the combined organic phases are dried over sodium sulphate and evaporated. The residue is crystallized at 0° C. in 300 ml of methanol. The solid is filtered off with suction, washed with cold methanol and dried. 20 g (32%) of the title compound are isolated as a pale yellow solid (m.p. 103-105° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].[CH2:15](Br)/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18]>CN(C=O)C>[CH3:18]/[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:16]\[CH2:15][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: O=c1ccc2cc(O)ccc2o1
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/COc1ccc2oc(=O)ccc2c1
Temperature: 0 °C

Procedure:
An oven-dried 50 mL round bottom flask was prepared with a magnetic stirring bar, a rubber septum cover, and a nitrogen inlet. 6-hydroxycoumarin (1) (114 mg, 0.7 mmol) and 4 mL of anhydrous DMF were added to the round bottom flask. The solution was stirred and cooled to 0° C. in a salt-ice bath. Sodium hydride (28 mg of 60% mineral oil suspension, 0.7 mmol) was added to the flask and the solution was kept stirring at 0° C. for 30 minutes. Geranyl bromide (329 μL, 1.66 mmol) in 1 mL of anhydrous DMF was cooled to 0° C. and added dropwise to the flask through the rubber septum using a syringe. The reaction mixture was left stirring under nitrogen at room temperature for 14 hours. The desired product was isolated by column chromatography using a solvent system of 100% Hexanes, 20:1 Hexanes:Ethyl acetate, 15:1 Hexanes:Ethyl acetate, 10:1 Hexanes:Ethyl acetate, 7:3 Hexanes:Ethyl acetate, and 2:1 Hexanes:Ethyl acetate. The purified product was characterized by NMR spectroscopy (1H-NMR, 13C-NMR) and high-resolution mass spectrometry (FIRMS). 1H-NMR (300 MHz, CDCl3): δ 1.61-1.84 (911), 2.13 (m, 4H), 4.57 (d, 2H, J=6 Hz), 5.1 (m, 1H), 5.48 (t, 1H), 6.43 (d, 1H, J=9 Hz), 6.93-7.67 (4H); 13C-NMR (75 MHz, CDCl3): δ 18.0, 18.2, 26.25, 26.38, 39.06, 65.20, 111.08, 117.01, 117.83, 118.89, 119.14, 119.70, 123.88, 13194, 141.44, 143.27, 148.41, 155.33, 161.06. FIRMS (Cl) Calcd. for C19H23O3: 299.16473. found: 299.16377.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4](O)([C:19]([F:22])([F:21])[F:20])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[NH:7][C:6]=1[CH3:18].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:7]=[C:6]1[CH3:18])[C:19]([F:21])([F:20])[F:22]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(F)cc2)c1=O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(=C1C(=O)N(c2ccc(F)cc2)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 1-(4-fluorophenyl)-2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (171 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11](=O)[CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.C(O)C.C(O[CH:20](OCC)[CH2:21][NH:22][NH2:23])C.Cl>O1CCOCC1.C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:11]([CH3:12])=[N:23][N:22]3[CH:21]=[CH:20][NH:10][C:9]=23)=[CH:4][CH:3]=1
Reactant: CC(=O)C(C#N)c1ccc(C)cc1
Reactant: CCOC(CNN)OCC
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc(-c2c(C)nn3cc[nH]c23)cc1
Yield: 72.3 %

Procedure:
A mixture of 1.7 g of 2-(4-methylphenyl)-3-oxo-butyronitrile, 20 ml of ethanol and 1.5 g of 2,2-diethoxyethylhydrazine was heated under reflux for 7 hours. At the end of this time, 30 ml of 4N hydrogen chloride in dioxane were added, and then the whole mixture was heated under reflux for a further 30 minutes. After the mixture had been cooled, diethyl ether was added to precipitate crystals. These were collected by filtration and partitioned between ethyl acetate and dilute aqueous ammonia. The organic phase was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to leave a residue, which was recrystallized from a mixture of ethyl acetate and hexane, to give 1.5 g of the title compound. The physical and chemical properties of this compound were the same as those of the compound prepared as described in Example 36.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:41][C@H:42]1[CH2:47][CH2:46][C@H:45]([NH:48][C:49]2[CH:54]=[C:53]([C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([NH:61][CH2:62][C:63]4[CH:68]=[CH:67][CH:66]=[C:65]([F:69])[CH:64]=4)[N:56]=3)[C:52]([Cl:70])=[CH:51][N:50]=2)[CH2:44][CH2:43]1>CS(C)=O.CN1C(=O)CCC1>[Cl:70][C:52]1[C:53]([C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([NH:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[C:65]([F:69])[CH:64]=3)[N:56]=2)=[CH:54][C:49]([NH:48][C@H:45]2[CH2:44][CH2:43][C@H:42]([NH:41][C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[CH2:47][CH2:46]2)=[N:50][CH:51]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-(dimethylamino)acetic acid (6.05 mg, 0.059 mmol), NMP (0.5 ml), Huenig's Base (0.023 ml, 0.132 mmol), and HATU (24.55 mg, 0.065 mmol) was stirred at ambient temperature for 5 minutes, followed by addition of N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(3-fluorobenzyl)-2,4′-bipyridine-2′,6-diamine (Example 1) (12.5 mg, 0.029 mmol). The resulting mixture was stirred at ambient temperature for 4 hours. The crude reaction mixture was diluted with 0.25 ml of DMSO, filtered, purified by prep LC and then lyapholized to yield 6.8 mg of the title compound, as a TFA salt. LCMS (m/z): 511.3 (MH+), retention time=0.62 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.32-1.53 (m, 4H) 1.98-2.07 (m, 2H) 2.07-2.18 (m, 2H) 2.92 (s, 6H) 3.60-3.68 (m, 1H) 3.70-3.82 (m, 1H) 3.90 (s, 2H) 4.63 (s, 2H) 6.83 (d, J=8.79 Hz, 1H) 6.86 (s, 1H) 6.93 (d, J=7.03 Hz, 1H) 6.99 (s, 1H) 7.10 (d, J=9.67 Hz, 1H) 7.18 (d, J=7.62 Hz, 1H) 7.28-7.40 (m, 1H) 7.68-7.77 (m, 1H) 8.01 (s, 1H)