Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][CH:19]=3)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnc2cc(Cl)ccc2c1Cl
Solvent: O
Product: O=[N+]([O-])c1cnc2cc(Cl)ccc2c1Nc1ccc(F)cc1

Procedure:
1.3 g (5.3 mmol) 4,7-dichloro-3-nitro-quinoline (Example 15b) and 0.525 g (5.3 mmol) 4-fluoroaniline are stirred at rt for 1 h. The reaction mixture is poured into 150 ml of water, and the resulting crystals are filtered off. After washing with water, the solid is dissolved in ca. 170 ml of ethanol and then concentrated to ca. 30 ml. The solution is cooled in ice-water. The crystals which precipitate are filtered off and dried overnight at 70° C. (high vacuum). mp: 198-200° C.; MS: 318 (M++1); HPLC: tret=10.92 min (Grad 1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][CH:26]([C:22]2[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=2)[CH2:27][CH2:28]1
Reactant: COc1ccccc1OCCCCCl
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: COc1ccccc1OCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-(4-chlorobutoxy)-2-methoxybenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]=CC=CC>>[CH3:12][CH:10]1[CH2:9][CH:8]=[CH:7][CH:3]2[C:4]([O:6][C:1](=[O:11])[CH:2]12)=[O:5]
Reactant: C=CC=CC
Reactant: O=C1OC(=O)c2ccccc21
Product: CC1CC=CC2C(=O)OC(=O)C12

Procedure:
The Diels-Alder adduct from phthalic anhydride and piperylene is hydrolysed and partially oxidized as in Example 10 and further oxidized as in Example 11. Similar results are obtained.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]2)[CH2:12][N:11]([C@H](C2C=CC=CC=2)C)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[CH2:34]([O:33][C:31]([N:11]1[CH2:12][C@@H:13]([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]2)[C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2])[CH2:10]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C1([C@@H]2CN([C@@H](C)c3ccccc3)C[C@H]2O[Si](C)(C)C(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Product: CCOC(=O)C1([C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O[Si](C)(C)C(C)(C)C)CC1

Procedure:
3-(S)-Tert-butyldimethylsilyloxy-4-(R)-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]pyrrolidine (5.48 g, 13.15 mnmol) was dissolved in dry dichloroinethane (120 ml), and benzyl chloroformate (3.76 ml, 26.3 mmol) was added dropwise to the thus prepared solution which was cooled in an ice bath. After heating the reaction solution under reflux for 2 hours, dichloroinethane was evaporated under reduced pressure. Thereafter, the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=5:1, to thereby obtain 4.52 g (77%) of the title coinpound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:38])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][C:21]([O:27]CC3C=CC(OC)=CC=3)=[C:22]([O:24][CH2:25][CH3:26])[CH:23]=2)=[CH:14][C:13]=1[F:37].Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:38])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[C:21](=[O:27])[NH:20][CH:19]=2)=[CH:14][C:13]=1[F:37]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3cc(F)ccc3F)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: Cl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(F)ccc3F)c(F)c2)c[nH]c1=O
Yield: 16.3 %

Procedure:
A solution of N-(2,5-difluorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (45 mg, 0.086 mmol) in HCl (MeOH (solvate), 64.6 μl, 0.258 mmol) was stirred at 20° C. for 1 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo to give crude product which was purified by preparation HPLC to afford pure product N-(2,5-difluorophenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (5.83 mg, 0.014 mmol, 16.8% yield): 1H NMR: (400 MHz, CD3OD) δ 7.86 (broad s, 1H), 7.43-7.37 (m, 5H), 7.20-7.13 (m, 1H), 6.86 (t, J=8.4 Hz, 1H), 4.20-4.15 (m, 2H), 3.88 (s, 2H), 1.48 (t, J=7.0 Hz, 3H); ES-LCMS: m/z 403.0 (M+H).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[N:23][C:24]=2[NH:28][CH2:29][CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)C.[O-]CC.[Na+].C(O)(=O)C>C(O)C>[OH:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[N:23][C:24]=2[NH:28][CH2:29][CH:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
To a solution of crude ethyl 9-{(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-[(acetyloxy)methyl]tetrahydro-2-furanyl}-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 64) (74.9 g, assumed 0.103 moles) in warm absolute ethanol (330 ml) was added sodium ethoxide (1.2 g, 0.018 moles) in portions over 23 hours. The resultant mixture was stirred for a further 3 hours and then glacial acetic acid (1.5 ml) was added. The mixture was concentrated in vacuo to give the crude product as a light brown foam (63.7 g) that was used as such for the next step. The crude product can be purified by flash chromatography on silica gel eluting with a gradient system of 5% v/v isopropanol in dichloromethane changing to 7.5% v/v isopropanol in dichloromethane changing to 10% v/v isopropanol in dichloromethane followed by crystallisation from tertiary-butyl methyl ether to give the title compound as colourless crystals, m.p. 118–120° C.
Reaction SMILES: CN(C)[C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:17][C:16]=1[F:28].[OH-:31].[Na+]>CCO>[CH:11]1([C:9]2[CH:8]=[CH:7][C:6]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][C:16]=3[F:28])=[C:5]([CH2:4][C:3]([OH:29])=[O:31])[CH:10]=2)[CH2:13][CH2:12]1
Reactant: [OH-]
Reactant: CN(C)C(=O)Cc1cc(C2CC2)ccc1Nc1ccc(-c2ccc(F)cc2)cc1F
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1cc(C2CC2)ccc1Nc1ccc(-c2ccc(F)cc2)cc1F

Procedure:
A solution of N,N-dimethyl-5-cyclopropyl-2-[2′-fluoro-4′-(4-fluorophenyl)anilino]phenylacetamide (575 mg) in 10 mL of 4 N NaOH and 20 mL of EtOH is heated overnight at 80° C. After cooling, the EtOH is removed under reduced pressure and the residue is diluted with EtOAc and cold water. The mixture is cooled in an ice bath and cold 2.5 N HCl is added until the pH of the aqueous layer reaches 2. The organic phase is separated, washed with brine, dried (Na2SO4) and concentrated in vacuo to give a brown solid. The solid is purified by flash chromatography eluting with 10%, then 20%, then 30% EtOAc in hexane to give the title product, m.p. 182–183° C.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=O>O>[CH3:1][NH:2]/[C:4](=[CH:5]\[CH3:7])/[C:3]([O:9][CH3:10])=[O:8]
Reactant: CN
Reactant: COC(=O)CC(C)=O
Solvent: O
Product: C/C=C(\NC)C(=O)OC
Temperature: 20 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
At 5° to 10° C., 186 g (2.4 moles) of a 40% strength aqueous methylamine solution is dripped into a solution of 232 g (2 moles) of methyl acetoacetate in 150 ml of water. The mixture is then stirred for 12 hours at room temperature (20° C.). The product is then separated from the solution by suction filtration. After washing with ice water and drying under reduced pressure, there is obtained 212 g (82%) of a white solid; m.p.: 62°-63° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])=[C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)[CH:14]=1
Reactant: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CN
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 474 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 9.00-6.55 (m, 10H), 4.90-2.80 (m, 5H), 1.95-0.65 (m, 8H).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H][H]>O1CCCC1>[CH2:1]1[CH:13]2[CH:5]([CH:6]3[CH:11]([CH2:12]2)[CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Product: C1CCC2C(C1)CC1CCCCC12
Reaction time: 16 h

Procedure:
A sample of 0.5 g (2.8 mmol) 9-fluorenone (Aldrich, 98%), 0.15 g Au—Pd/SiO2/TiO2 catalyst and 5 ml tetrahydrofuran (Fisher, HPLC Grade) were placed in a 20 cc stirred tank reactor and the reactor was sealed. The reactor was connected to a manifold containing a vacuum source, high-pressure hydrogen source, and a high-pressure ballast. After evacuation of residual air from the manifold lines, hydrogen was purged through the reactor to displace the air from the reactor headspace. The mixture was hydrogenated at 110 psia H2 pressure and 70° C. for 16 hours. After cooling the reactor and venting the reactor to atmospheric pressure, the contents of the reactor were filtered to remove the catalyst. GC-MS analysis of the product showed complete conversion of 9-fluorenone to two products: fluorene (53.5%) and hexahydrofluorene (46.5%). To this solution of fluorene and hexahydrofluorene was added 0.15 g of a ruthenium supported on alumina catalyst (Engelhard, 5% Ru) and the slurry was returned to the reactor. The mixture was hydrogenated at 1000 psia H2 pressure and 190° C. for 4 hours. After cooling and venting the reactor to atmospheric conditions, the catalyst was removed by filtration. GC-MS analysis of the product solution showed >99% conversion and >99% selectivity to perhydrofluorene. The cis,cis isomer of perhydrofluorene was obtained with 96% selectivity based on the GC retention time vs. commercial perhydrofluorene (Aldrich, 97%). INADEQUATE 13C NMR of the commercial perhydrofluorene confirmed the cis-cis stereochemistry of the four methine carbons in the central ring: 22.1 ppm (s), 24.3 ppm (s), 24.4 ppm (s), 29.2 ppm (s), 35.3 ppm (s), 37.3 ppm (s), 43 ppm (s), confirmed the cis-cis stereochemistry of the four methine protons in the central ring as reported by R. Meusinger in J. Prakt. Chem. 339, 128 (1997).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:31])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C:17]([OH:22])([CH3:21])[C@H:16]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1[C:40]1[N:45]=[C:44]([C:46](O)=[O:47])[CH:43]=[CH:42][C:41]=1[F:49].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC#N>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:31][C:46]([C:44]3[CH:43]=[CH:42][C:41]([F:49])=[C:40]([C:34]4[C:33]([F:32])=[CH:38][CH:37]=[CH:36][C:35]=4[F:39])[N:45]=3)=[O:47])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C:17]([OH:22])([CH3:21])[C@H:16]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C(C)(O)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cccc3F)n1)c2N1C[C@H](C)C(C)(O)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
3-Amino-4-{(3R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (153 mg, 0.352 mmol), 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (107 mg, 0.422 mmol), HATU (330 mg, 0.88 mmol), and DIPEA (180 μL, 1.0 mmol) were dissolved in DMF (4.9 mL) and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with MeCN and purified by RP-HPLC (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μm particle size, eluting with a gradient of MeCN/water containing 0.1% TFA, at flow rate of 30 mL/min.) to give the sub-title compound as a white solid (118 mg, 50%). LCMS calc. for C34H39F3N5O6 (M+H)+ m/z=670.3. found 670.3.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][Cl:25])[CH3:19].C([O-])([O-])=O.[Na+].[Na+].Cl>C(#N)C>[ClH:25].[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:9]1[CH2:8][CH2:7][C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:11][CH2:10]1)[CH3:19]
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Reactant: CCOCCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOCCCCN1CCC(C(=O)OCC)(c2ccccc2)CC1
Reaction time: 72 h

Procedure:
Norpethidine (15.63 g, 67 mmol), 4-ethoxybutylchloride (10.67 g, 70 mmol), Na2CO3 (7.77 g, 73 mmol), KI (0.6 g) and acetonitrile (150 ml) were heated under reflux and stirring for 72 h. The mixture was filtered and the solvent removed. The residue was dissolved in diethyl ether, and the solution washed with water and dried (MgSO4). Destillation yielded 17.9 g of base boiling at 160°-163° C./0.05 mm Hg. B.p. acc. to J. Chem. Soc. 3062 (1958) 180° C./1 mm Hg. Hydrochloride m.p. 143°-145° C.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:40])[CH:26]=[C:27]([CH:28]([CH3:30])[CH3:29])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:43][N:42]=[N:41][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:40])[CH:26]=[C:27]([CH:28]([CH3:29])[CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C(C)C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C(C)C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-isopropyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9]1)(=O)=O.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K]>CN(C)C=O>[O:24]=[C:22]1[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19](=[O:29])[N:23]1[CH2:6][CH2:7][C:8]1([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(CCOS(C)(=O)=O)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(CCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 150 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
To a solution of 7.82 g (28 mmol) of 2-{1-[(tert-butoxycarbonyl)amino]-cyclopropyl}ethyl methanesulfonate in 35 ml of anhydrous dimethylformamide was added 5.45 g (29.4 mmol) of potassium phthalimide. The resulting mixture was stirred at 150° C. for 18 h. The mixture was then filtered and washed with diethyl ether. The filtrate was evaporated to dryness, the crude product was heated in water and the precipitate was filtered. The product was dried to give 4.63 g of pure compound as an orange solid. Mp: 125-127° C.
Reaction SMILES: [C:1]1([CH2:17]O)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.P(Br)(Br)[Br:20].N#N.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]1([CH2:17][Br:20])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: OCc1ccc2ccc3cccc4ccc1c2c34
Reactant: BrP(Br)Br
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: BrCc1ccc2ccc3cccc4ccc1c2c34
Reaction time: 12 h

Procedure:
Firstly, 500 mg of (1-pyrenyl)methanol as the starting material was dissolved in 20 mL of dehydrated dichloromethane, and then 1 mL of PBr3 was slowly dropped into the solution that was kept in an ice bath of 0° C. in an N2-atmosphere. After 12 hours of stirring with a magnetic stirrer, the mixture was neutralized with 50 ml of 0.3M sodium bicarbonate solution (4 g/150 mL) three times using a separating funnel, and then CH2Cl2 was used to extract the organic phase in the mixture. After the moisture in the organic phase was removed by anhydrous MgSO4, the solvent in the organic phase was removed under a reduced pressure to obtain 547 mg of (1-pyrenyl)bromomethane in a high purity. The completion of the bromination was confirmed by the 1H-NMR spectrum of the product in FIG. 3A and the mass spectrum (molecular weight=295.17) of the same.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]([C:21]([NH2:23])=[O:22])=[CH:11][C:12]3[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][O:14][C:13]=3[CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.N(CCO)CCO>C(Cl)Cl>[CH:1]1([CH2:7][O:8][C:9]2[C:10]([C:21]([NH2:23])=[O:22])=[CH:11][C:12]3[C@H:18]([OH:19])[CH2:17][CH2:16][CH2:15][O:14][C:13]=3[CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC(=O)c1cc2c(cc1OCC1CCCCC1)OCCCC2=O
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: ClCCl
Solvent: OCCNCCO
Product: NC(=O)c1cc2c(cc1OCC1CCCCC1)OCCC[C@H]2O
Temperature: -12 °C
Reaction time: 18 h

Procedure:
To 8-cyclohexylmethoxy-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-7carboxylic acid amide (4.0 g, 13.3 mmol) suspended in CH2Cl2 (25 mL) at 42° C. was added (+)-DIP-Chloride (25 mL of CH2Cl2). The mixture was stirred at −12° C. for 18 h, concentrated, diluted with Et2O (200 mL) and treated with diethanolamine (5.1 mL, 53.1 mmol). After stirring for 2.5 h, the formed solids were filtered and washed with Et2O. The filtrate was concentrated, and the residue purified by silica gel column chomatography (5% MeOH/CH2Cl2) to a white solid (3.2 g, 80%). m.p. 164-165° C. Optical purity determined by Mosher Amide formation, 71% e.e.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[O:12][CH2:8][C:7]1[CH:11]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(O)c(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 5-methoxysalicylic acid (33.6 g., 0.2 mol) in 300 ml. of hexamethylphosphorustriamide is treated successively with 16 g. of sodium hydroxide in 40 ml. of water and 68.4 g. (0.4 mol) of benzyl bromide. The resulting solution is stirred 14 hours at room temperature, poured into water and extracted with diethyl ether. The ether solution is dried and evaporated to a yellow oil which solidified on standing. Recrystallization from benzenehexane gives the desired 2-benzyloxy-5-methoxy benzoic acid benzyl ester.
Reaction SMILES: C(OC([NH:8]C1C(B(O)O)=CC=CN=1)=O)(C)(C)C.Cl.C(=O)([O-])[O-].[Na+].[Na+].[CH3:25][CH:26]([CH3:45])[CH2:27][C:28]1[N:29]([CH2:42][CH2:43][CH3:44])[N:30]=[C:31]2[C:40]=1[C:39]1[CH:38]=[CH:37][CH:36]=C[C:34]=1[N:33]=[C:32]2[NH2:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)CC.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][CH:26]([CH3:45])[CH2:27][C:28]1[N:29]([CH2:42][CH2:43][CH3:44])[N:30]=[C:31]2[C:40]=1[C:39]1[CH:38]=[CH:37][CH:36]=[N:8][C:34]=1[N:33]=[C:32]2[NH2:41]
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)C
Reactant: CC(C)(C)OC(=O)Nc1ncccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCO
Product: CCCn1nc2c(N)nc3ncccc3c2c1CC(C)C
Yield: 11.2 %

Procedure:
A modification of the method described in Example 16 was used to treat 2-tert-butoxycarbonylamino-3-pyridylboronic acid (11.33 mmol) in 1-propanol (10 mL) with hydrochloric acid (12 mL of 1 M) followed by sodium carbonate (1.99 g, 18.8 mmol), 4-bromo-5-(2-methylpropyl)-1-propyl-1H-pyrazole-3-carbonitrile (1.53 g, 5.66 mmol, prepared as described in Example 1) in 1-propanol (5 mL), triphenylphosphine (44.5 mg, 0.17 mmol), and palladium (II) acetate (13 mg, 0.057 mmol) in toluene (0.25 mL). The reaction was complete after it was heated overnight. Following the work-up procedure and purification, 0.18 g of 1-(2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amine was obtained as off-white needles, mp 257-260° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5](=[O:14])[C:4]=1[C:15]([NH:17][CH2:18][C:19]([O:21]C)=[O:20])=[O:16].[OH-].[Na+].ClCCl.O>C1COCC1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5](=[O:14])[C:4]=1[C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16]
Reactant: COC(=O)CNC(=O)c1c(OC)c2ccccc2n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COc1c(C(=O)NCC(=O)O)c(=O)n(C)c2ccccc12
Reaction time: 1.5 h

Procedure:
Methyl 2-(4-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.150 g, 0.5 mmol) was dissolved in THF in a 25 mL round bottom flask. NaOH was added and the mixture was stirred for 1.5 hours. Dichloromethane and water were added to the reaction and the layers were separated. The aqueous layer was washed two more times with dichloromethane. To the aqueous phase, IN HCL was added until the pH was approximately 1. The aqueous phase was then extracted with 25% IPA/CHCl3, dried with MgSO4 and concentrated on a roto-evaporator. The compound was then purified by HPLC to give the desired product as a white solid.