Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][C@@H:30]([CH3:36])[C:31]([NH:33][CH2:34][CH3:35])=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:34]([NH:33][C:31]([C@@H:30]([NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:36])=[O:32])[CH3:35]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCNC(=O)[C@H](C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)[C@H](C)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((S)-1-ethylcarbamoyl-ethyl)-amide (37 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), (S)-2-amino-N-ethyl-propionamide (0.37 ml), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 508. 1H NMR (DMSO-d6, 400 MHz): δ 8.38 (d, 1H), 8.13 (s, 1H), 7.92 (s, 2H), 7.86 (br, 1H), 7.73 (br, 1H), 7.48 (d, 1H), 7.36 (d, 1H), 4.46 (p, 1H), 3.66 (s, 3H), 3.12-3.09 (m, 2H), 1.34 (d, 3H), and 1.04 (t, 3H), NH proton signal was not observed.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=3)[CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cn1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.2) (0.22 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure III. Obtained as a yellow solid (0.2 g, 87%). MS (ISP) 462.2 [(M+H)+]; mp 244° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([CH3:20])=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F-].[K+].[C:32]1([S:38]([C:41]([S:63]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)(=[O:65])=[O:64])([F:62])[CH:42]([C:52]2[C:60]3[C:55](=[N:56][CH:57]=[C:58](Br)[CH:59]=3)[NH:54][CH:53]=2)[C:43]2[C:48]([Cl:49])=[CH:47][CH:46]=[C:45]([F:50])[C:44]=2[Cl:51])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O1CCOCC1.O>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([CH3:20])=[C:18]([C:58]3[CH:59]=[C:60]4[C:52]([CH:42]([C:43]5[C:48]([Cl:49])=[CH:47][CH:46]=[C:45]([F:50])[C:44]=5[Cl:51])[C:41]([F:62])([S:63]([C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=5)(=[O:64])=[O:65])[S:38]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)(=[O:39])=[O:40])=[CH:53][NH:54][C:55]4=[N:56][CH:57]=3)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: O=S(=O)(c1ccccc1)C(F)(C(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12)S(=O)(=O)c1ccccc1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2cnc3[nH]cc(C(c4c(Cl)ccc(F)c4Cl)C(F)(S(=O)(=O)c4ccccc4)S(=O)(=O)c4ccccc4)c3c2)cnn1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (202.16 mg, 0.48079 mmol), Potassium fluoride (76.18 mg, 1.311 mmol) and 3-[2,2-Bis-benzenesulfonyl-1-(2,6-dichloro-3-fluoro-phenyl)-2-fluoroethyl]-5-bromo-1H-pyrrolo[2,3-b]pyridine (300.00 mg, 0.43708 mmol) in 1,4-Dioxane (10.00 mL, 128.1 mmol) and H2O (2.500 mL, 138.8 mmol) was added (1,1′-bis-(diphenylphosphino)-ferrocene) palladium dichloride (15.99 mg, 0.02185 mmol) under Nitrogen atmosphere, the resulting mixture was then stirred at 90° C. for 90 min. Then the solvent was removed under reduced pressure to give a residue, which was purified by silica gel chromatography (eluent: 20-30% AcOEt in DCM) to give the title compound. MS (ES+): m/z 899.20, 901.21 [MH+]. HPLC: tR=1.98 min (polar—3 min, TOF).
Reaction SMILES: CN(CC1CC(OC2C=CC(CN3CCCC3)=CC=2)C1)S(CC(F)(F)F)(=O)=O.[CH2:29]([N:36]([CH3:44])[C:37]([CH:39]1[CH2:42][C:41](=[O:43])[CH2:40]1)=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1.O>[CH2:29]([N:36]([CH2:37][C@@H:39]1[CH2:40][C@H:41]([OH:43])[CH2:42]1)[CH3:44])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN(Cc1ccccc1)C(=O)C1CC(=O)C1
Agent: CN(CC1CC(Oc2ccc(CN3CCCC3)cc2)C1)S(=O)(=O)CC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccccc1)C[C@H]1C[C@@H](O)C1

Procedure:
A solution of intermediate 2, N-benzyl-N-methyl-3-oxocyclobutanecarboxamide (27.9 g, 0.128 mol) in absolute THF (40 mL) was added to a suspension of LiAlH4 (9.75 g, 0.257 mol) in absolute THF (200 ml) under stirring in argon. The mixture was refluxed under stirring for 1 h and cooled. Then 10 N NaOH (25 mL) and water (25 mL) were added. The organic layer was decanted, and the aqueous one was extracted with THF (2×50 mL). The organic layers were evaporated. The residue was purified by chromatography (silica gel, 63-100 μm, 300 g, CHCl3/MeOH 100:0→90:10). The title compound (25 g, 95%) was obtained as a colorless oil. 1H NMR-data (DMSO-d6): 7.19-7.33 (m, 5H, Ph); 4.85 (d, 1H, OH, J=6.6 Hz); 3.83-3.94 (m, 1H); 3.40 (s, 2H, CH2); 2.24-2.34 (m, 4H); 2.07 (s, 3H, NCH3); 1.81-1.92 (m, 1H); 1.34-1.44 (m, 2H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>CCCCCC.O1CCCC1>[CH3:24][Si:23]([CH3:26])([CH3:25])[O:18][C:13]([O:19][CH2:20][CH3:21])=[CH:14][CH:15]([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)CC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=CC(C)C)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 1 liter flask was equipped with a mechanical stirrer, a reflux condenser, an addition funnel, nitrogen inlet, and thermometer. The glassware was dried carefully and charged with 225 ml of tetrahydrofuran, 30.36 g (0.300 mol) of diisopropylamine, and cooled to 0° C. Over a 30 minute period, 190 ml (0.300 mol) of 1.6 M n-butyl lithium in hexane was added. The reaction mixture was stirred at 0° C. for 15 min., then cooled to -76° C. and 39.06 g (0.300 mol) of ethyl isovalerate added dropwise over ~15 min. When addition was complete, the reaction mixture was stirred for 15 min. at -76° C., then 82 ml (0.88 mol) of chlorotrimethylsilane added dropwise. When addition was complete, the Dry Ice-acetone bath was removed and the reaction mixture stirred for 11/2 hrs. while coming up to room temperature.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH2:18][CH2:19][O:20][C:21]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)=[CH:24][C:22]=3[CH:23]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(OCC)(=O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([C:17]2[CH2:18][CH2:19][O:20][C:21]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=4)=[CH:24][C:22]=3[CH:23]=2)=[O:16])[CH2:12][CH2:13]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)CCO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCNCC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To N-[1-(t-butoxycarbonyl)piperidin-4-yl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (1.56 g) dissolved in ethyl acetate (100 ml) was added 4 N hydrochloric acid/ethyl acetate (25 ml), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was mixed with a 1 N aqueous solution of sodium hydroxide and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and then was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 54) (1.1 g) as colorless prisms.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[C:13]([F:18])[CH:12]=2)[CH2:6]1)=[N+]=[N-].[C:19]([OH:22])(=S)[CH3:20]>>[F:18][C:13]1[CH:12]=[C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][NH:1][C:19](=[O:22])[CH3:20])[O:9][C:8]2=[O:10])[CH:16]=[CH:15][C:14]=1[I:17]
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: CC(O)=S
Product: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(5R)-5-(Azidomethyl)-3-(3-fluoro-4-iodophenyl)-1,3-oxazolidin-2-one (Intermediate 5, 5.00 g, 0.014 mol) was suspended in thioacetic acid (10 ml) and the solution was stirred under nitrogen at room temperature for ca. 16 h. The resulting suspension was concentrated under vacuum. The crude product was crystallized from methanol/acetone, then further purified by chromatography on silica gel using dichloromethane to give 3.71 g of the title product as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([C:18]3[CH:23]=[N:22][C:21]([O:24][CH3:25])=[N:20][CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:3]=1
Reactant: COc1ncc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cn1
Reactant: COc1cccc(B(O)O)c1F
Product: COc1ncc(C2(c3cccc(-c4cccc(OC)c4F)c3)N=C(N)c3ccccc32)cn1
Yield: 27 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-methoxypyrimidin-5-yl)-1H-isoindol-3-amine (Example 106) as described in Example 67 Scheme #10, D in 27% yield using 2-fluoro-3-methoxyphenylboronic acid. 1H NMR (DMSO-d6) δ 8.55 (s, 2H), 7.96-7.79 (m, 2 H), 7.58-7.43 (m, 3 H), 7.43-7.34 (m, 3 H), 7.24-7.12 (m, 2 H), 7.08-6.83 (m, 3 H), 3.88 (s, 3 H), 3.86 (s, 3 H); MS (ESI) m/z 441 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.[CH3:11][O:12][C:13](=[O:22])[C@:14]([N:19]=[C:20]=[O:21])([CH:16]([CH3:18])[CH3:17])N>CN(C)C1C=CN=CC=1.ClCCl>[CH3:11][O:12][C:13](=[O:22])[C@H:14]([CH:16]([CH3:17])[CH3:18])[NH:19][C:20]([O:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1)=[O:21]
Reactant: CC(C)c1nc(CO)cs1
Reactant: COC(=O)[C@](N)(N=C=O)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)OCc1csc(C(C)C)n1)C(C)C
Yield: 56.6 %

Procedure:
A solution of 2.18 g (15 mmol) of 4-(hydroxymethyl)-2-isopropylthiazole, 15.8 mmol of α-isocyanato-valine methyl ester and 1.5 mmol of 4-dimethylaminopyridine in 75 ml of dichloromethane was heated at reflux for 5 h. The resulting solution was washed successively with 10% citric acid, aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. Silica gel chromatography of the residue using 5% ethyl acetate in chloroform provided 2.67 g (57%) of the pure desired compound, Rf 0.46 (4% methanol in chloroform). NMR 1H NMR (DMSO-d6) δ1.26 (d, J=8 Hz, 3H), 1.32 (d, J=7 Hz, 6H), 3.27 (heptet, J=7 Hz, 1H), 3.63 (s, 3H), 4.10 (pentet, J=8 Hz, 1H), 5.02 (s, 2H), 7.47 (s, 1H), 7.8 1 (d, J=8 Hz, 1H). Mass spectrum: (M+H)+ =287.
Reaction SMILES: [NH2:1][C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70]([NH:72][CH2:73][C:74]4[CH:79]=[CH:78]C=[CH:76][N:75]=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.N1C=CC(CN)=NC=1>>[ClH:45].[C:94]1([CH:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70]([NH:72][CH2:73][C:74]4[CH:79]=[CH:78][N:1]=[CH:76][N:75]=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:95]=[CH:96][CH:97]=[CH:98][CH:99]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Agent: NCc1ccncn1
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccncn6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with C-pyrimidin-4-yl-methylamine. MS (ES+) m/e 731.46 (MH+)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:3]1)=[O:21]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: NC1CCC(CNc2ccccc2)CC1
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](CNc2ccccc2)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 7 mL vial equipped with magnetic stirrer bar is added (4-Amino-cyclohexylmethyl)-phenyl-amine (41 mg, 0.2 mmol), 3-chlorobenzoyl chloride (20 mg, 0.16 mmol) and DCM (2 mL) followed by trethylamine (42 μL, 0.3 mmol). The mixture is stirred at room temperature under nitrogen atmosphere for 3 hours. The mixture was then evaporated to dryness and purified directly by preparative HPLC, [MH+343.19].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][CH2:12][CH2:13][N:14]1[C:26]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:16]=[CH:15]1)(=O)C>CO>[N:14]1([CH2:13][CH2:12][CH2:11][OH:10])[C:26]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:16]=[CH:15]1
Reactant: CC(=O)OCCCn1cnc2cnc3cccnc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCCCn1cnc2cnc3cccnc3c21
Reaction time: 3 h
Yield: 16.3 %

Procedure:
Solid potassium carbonate (2.68 g, 19.4 mmol) was added to a solution of 3-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propyl acetate (3.50 g, 12.9 mmol) in methanol (65 mL) at room temperature. The mixture was stirred for 3 hours, then the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (150 mL) and water (75 mL). The organic layer was washed with brine (75 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a brown semi-solid that was triturated with dichloromethane and isolated by filtration to afford 0.48 g of 3-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propan-1-ol. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-50% CMA in chloroform) to provide an additional 0.67 g of 3-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propan-1-ol.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9]2)[CH:3]=1.[C:23]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)(=O)C>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:9]2)[C:3]=1[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: O=C1CCCCC1
Reactant: Cn1nc(C2CCN(C(=O)OCc3ccccc3)C2)cc1N
Solvent: CC(=O)O
Product: Cn1nc(C2CCN(C(=O)OCc3ccccc3)C2)c(C2=CCCCC2)c1N
Yield: 52.8 %

Procedure:
A solution of EXAMPLE 24C (1.78 g, 5.92 mmol) and cyclohexanone (1.23 mL, 11.85 mmol) in acetic acid (10 mL) was stirred at ambient temperature overnight and at 55° C. for 1 day. The acetic acid was removed and the residue partitioned between sodium bicarbonate solution and ethyl acetate. The organic phase was washed with water, concentrated and the residue purified by flash chromatography on silica gel using 70-90% ethyl acetate in hexane to provide the title compound as a light yellow solid (1.19 g, 53%). MS (DCI): m/z 381 (M+H)+.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3B(O)O)=[N:11][N:10]=[N:9]2)C=CC=CC=1.[CH2:34]([N:38]1[CH:42]=[C:41]([CH2:43][CH2:44][CH2:45][CH3:46])[N:40]([CH2:47][C:48]2[CH:49]=[N:50][C:51](Br)=[CH:52][CH:53]=2)[C:39]1=[O:55])[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:34]([N:38]1[CH:42]=[C:41]([CH2:43][CH2:44][CH2:45][CH3:46])[N:40]([CH2:47][C:48]2[CH:49]=[N:50][C:51]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[NH:8][N:9]=[N:10][N:11]=3)=[CH:52][CH:53]=2)[C:39]1=[O:55])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCc1cn(CCCC)c(=O)n1Cc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCc1cn(CCCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reaction time: 14 h
Yield: 43 %

Procedure:
A solution of 21.7 g (50.2 mmol) of 2-(N-triphenylmethyltetrazol-5-yl)phenylboronic acid from step 6 in 80 mL of ethanol and 130 mL of toluene was added to a mixture of 5 g (4 mmol) of tetrakis (triphenylphosphine) Pd(0), 16.75 g (45.8 mmol) of 1,4-dibutyl-1,3-dihydro-3-[(6-bromo-3-pyridinyl) methyl]-2H-imidazol-2-one from step 5, 225 mL of toluene, 100 mL of 2 M sodium carbonate, and 150 mL of ethanol. The reaction mixture was heated to reflux and vigorously stirred under nitrogen for 14 h. The pH was adjusted to 6 with acetic acid and the reaction concentrated in vacuo. The product was purified by silica gel chromatography (Waters Prep-500A) using 2-propanol/methylene chloride (0-50%) followed by reverse phase chromatography (Waters Deltaprep-3000) using acetonitrile/water (30-35: 70-65) (0.05% TFA). The pure fractions (by analytical HPLC) were combined, the acetonitrile removed in vacuo, and the water extracted 4 times with chloroform. The extracts were combined, dried (MgSO4), and concentrated in vacuo. Recrystatlization from ethyl acetate gave 8.5 g (43%) of colorless 1,4-dibutyl-1,3-dihydro-3-[[6-[2-(1H-tetrazol-5-yl)phenyl]-3-pyridinyl]methyl]-2H-imidazol-2-one as a colorless solid: mp 170°-171° C.; NMR (CDCl3) δ0.88 (t, J=7 Hz, 3H), 0.96 (t, J=7 Hz, 3H), 1.28-1.54 (m, 6H), 1.61-1.72 (m, 2H), 2.28 (t, J=8 Hz, 2H), 3.63 (t, J=7 Hz, 2H), 4.96 (s, 2H), 5.96 (s, 1H), 7.36 (d, J=9 Hz, 1H), 7.47-7.58 (m, 3H), 7.67 (dd, J=9 and 2 Hz, 1H), 8.06-8.13 (m, 1H), 8.52 (d, J,=2 Hz, 1H); MS (FAB) m/e (tel intensity) 432 (100), 404 (18), (14), 209 (92), 180 (82); HRMS. Calc'd for M+H: 432.2512. Found: 432.2554. Anal. Calc'd for C24H29N7O: C, 66.80; H, 6.77; N, 22.72. Found: C, 66.59; H, 6.85; N, 22.57.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].N1C=CN=C1.[CH3:19][C:20]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])[CH3:21]>CN(C)C=O>[Si:23]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])([C:20]([CH3:22])([CH3:21])[CH3:19])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCOCCOCCOCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCOCCOCCOCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
A mixture of tetra(ethylene glycol) 9 (5.00 mL, 28.7 mmol) and imidazole (2.91 g, 42.6 mmol) was dissolved in 10 mL of N,N-dimethylformamide (DMF). TBDPSCl (7.80 mL, 29.4 mmol) was added to the solution dropwise over a 30 min-period using a syringe with an additional amount of DMF (total 20 mL) being added to avoid the reaction mixture becoming cloudy. The reaction was stirred at room temperature for 16 h. DMF was removed under reduced pressure and the crude product was chromatographed (SiO2, gradient, hexane/EtOAc 1:1 to 2:3) to give 6.05 g (14.0 mmol, 49%) of 10 as a light colorless oil. Rf 0.21 (hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3) δ 7.68 (m, 4H, H-2 of phenyl), 7.44-7.35 (m, 6H, H-3 and H-4 of phenyl), 3.81 (t, 2H, J=5.5 Hz, CH2OSi), 3.71 (m, 2H, HOCH2CH2), 3.68-3.58 (m, 12H, HOCH2CH2(OCH2CH2)2OCH2CH2), 2.46 (br s, 1H, OH), 1.05 (s, 9H, C(CH3)3); MS (ESI) Calcd for C24H36O5SiNa (M+Na+): 455.2. Found: 455.2.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:21][CH:20]3[CH:16]([CH2:17][NH:18][CH2:19]3)[CH2:15]2)=[O:13])[NH:4][CH:5]=1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=1.CCN(C(C)C)C(C)C>C(#N)C>[N:1]1[N:2]=[C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:15][CH:16]3[CH:20]([CH2:19][N:18]([C:23]4[N:28]=[C:27]([CH3:29])[C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=4)[CH2:17]3)[CH2:21]2)=[O:13])[NH:4][CH:5]=1
Reactant: Cc1nc(Cl)nc(C)c1C
Reactant: O=C(c1ccccc1-c1nnc[nH]1)N1CC2CNCC2C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CC3CN(C(=O)c4ccccc4-c4nnc[nH]4)CC3C2)nc(C)c1C
Yield: 28.8 %

Procedure:
The product of Step A (167 mg, 0.421 mmol), Intermediate 56 (66 mg, 0.421 mmol) and DIPEA (0.29 mL, 1.68 mmol) were heated for 2 h at 200° C. in ACN (1.4 mL) in the microwave. The mixture was concentrated in vacuo. The crude product was purified using Agilent HPLC (basic system) to yield impure material. This material was subsequently purified using normal phase chromatography (DCM to 8% 2M NH3 in MeOH/DCM) to afford the title compound (49 mg, 29%). MS (ESI) mass calculated for C22H25N7O, 403.49; m/z found, 404.2. 1H NMR (500 MHz, CDCl3): 8.16 (d, J=7.8 Hz, 1H), 8.06 (s, 1H), 7.54-7.49 (m, 1H), 7.48-7.44 (m, 1H), 7.35 (d, J=7.5 Hz, 1H), 3.96-3.89 (m, 1H), 3.85-3.77 (m, 1H), 3.74-3.68 (m, 1H), 3.68-3.55 (m, 2H), 3.42 (br s, 2H), 3.16 (br s, 1H), 3.04-2.96 (m, 1H), 2.89 (br s, 1H), 2.32 (s, 6H), 2.05 (s, 3H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].S(Cl)([Cl:12])=O>>[Cl-:12].[C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5]
Reactant: O=S(Cl)Cl
Agent: COC(=O)CCC(=O)[O-]
Product: [Cl-]

Procedure:
Methyl succinate (20.5 g) was heated with 20 ml thionyl chloride to 40° for 3.5 hours. Excess thionyl chloride was removed by vacuum distillation (13 mm Hg). The acid chloride (20.6 g) was distilled at 43°-44° /0.2 mm Hg.