Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[O:11]1[CH2:16]COC[CH2:12]1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[CH3:12][O:11][CH2:16][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Product: COCc1ccc(C(C)=O)cc1
Temperature: 100 °C
Reaction time: 7 h
Yield: 31 %

Procedure:
To a mixture of 4′-bromoacetophenone (300 mg, 1.51 mmol) and 1,4-dioxane (4 ml) were added water (0.4 ml), cesium carbonate (1.48 g, 4.54 mmol), potassium methoxymethyl trifluoroborate (459 mg, 3.02 mmol) and 1′,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (110 mg, 0.151 mmol). Then, the reaction mixture was stirred at 100° C. (external temperature) for 7 hours. After the reaction mixture was cooled at room temperature, water and methylene chloride were added to the mixture, followed by filtration using Celite. The separated organic layer was washed with an aqueous saturated sodium chloride solution. The organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate) to obtain the title compound (76 mg, 31%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:28]1[CH2:31][CH:30]([C:32]([O:34][CH3:35])=[O:33])[CH2:29]1.[BH3-]C#N.[Na+]>C(O)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:24]([F:25])([F:26])[F:27])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:28]2[CH2:31][CH:30]([C:32]([O:34][CH3:35])=[O:33])[CH2:29]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CNC1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2C(F)(F)F)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1CN(Cc2ccc3c(C(F)(F)F)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1

Procedure:
A mixture of 6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehyde (300 mg, 0.8 mmol) and methyl azetidine-3-carboxylate (184 mg, 1.6 mmol, 2.0 equiv) in anhydrous ethanol (20 mL) was refluxed for 2 h. Then the solvent was removed in vacuo, fresh ethanol and NaBH3CN (150 mg, 2.4 mmol, 3.0 equiv) was added, the resulting mixture was refluxed for 1 h. The reaction mixture was concentrated and the residue was purified by chromatography with silica gel (dichloromethane:methanol 20:1) to give product methyl 1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylate as a white solid (150 mg, yield: 40%). ESI-MS: 477.3 (M+H)+. HPLC: 85.67% 1H NMR (400 MHz, CD3OD) δ: 8.09 (dd, 1H), 8.01 (d, 1H), 7.56 (s, 1H), 7.46-7.51 (m, 2H), 4.42 (m, 1H), 3.77 (s, 2H), 3.71 (s, 3H), 3.57 (t, 2H), 3.45 (t, 2H), 3.35-3.39 (m, 1H), 2.18 (d, 2H), 1.88 (d, 2H), 1.43-1.52 (q, 2H), 1.09-1.22 (m, 3H), 0.89 (s, 9H)
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C(N(CC)CC)C>C(OCC)(=O)C>[N+:18]([C:12]1[CH:13]=[C:14]([NH:15][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:17][C:11]=1[F:10])([O-:20])=[O:19]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Reaction time: 2 h
Yield: 81.1 %

Procedure:
Benzoyl chloride (12 mL, 103 mmol) was added dropwise to 4-fluoro-3-nitroaniline (15.64 g, 100 mmol) and triethylamine (17 mL, 122 mmol) in ethyl acetate (400 mL) at room temperature. The reaction mixture was stirred for 2 hours and then allowed to stand overnight. The reaction mixture was washed with 10% aqueous citric acid solution (200 mL), saturated aqueous sodium bicarbonate solution (200 mL), and brine (100 mL); dried (magnesium sulfate), filtered, and concentrated to about 100 mL at which point a solid began to precipitate. The mixture was cooled to zero degrees and the straw-colored solid collected by filtration to afford the product (21.1 g) in two crops.
Reaction SMILES: O[C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11]([OH:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[N:9]1([O:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=[N:8]1
Reactant: O=C(O)c1ccccc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(On1nnc2ccccc21)c1ccccc1
Reaction time: 5 h

Procedure:
Hydroxybenzotriazole resin (0.107 g, 0.196 mmol) was treated with benzoic acid (0.12 g, 0.982 mmol, 5 eq), DIC (0.152 mL, 0.982 mmol, 5 eq) and DMAP (0.024 g, 0.196 mmol, 1 eq) in DMF-CH2Cl2 (1:1) and shaken for 5 h. The mixture was filtered and the resin was washed with DMF (10×5 mL) and CH2Cl2 (10×5 mL) to give resin-supported benzoic acid benzotriazol-1-yl ester. To a suspension of the resin-ester (0.196 mmol, 1.5 eq) in CH2Cl2 (2 mL) were added i-Pr2NEt (0.033 mL, 0.196 mmol, 1.5 eq) and 2-amino-2-methyl-pentan-3-one (0.03 g, 0.131 mmol, 1 eq). The mixture was agitated for 16 h and filtered. The filtrate was shaken with a weakly basic ion exchange resin Amberlite IRA-95 (1 g, 4.7 mmol g−1, 25 eq) for 16 h to remove benzoic acid present in the solution and filtered. The filtrate was eluted through a short column of silica gel (hexane/ethyl acetate 50:50) to remove the unreacted amine. The organic solvent was evaporated to leave N-(1,1-dimethyl-2-oxo-butyl)-benzamide (0.03 g, 87%) as a white solid. 1H NMR (200 MHz, CDCl3) δ (ppm): 1.14 (t, J=7.2 Hz, 3H), 1.57 (s, 6H), 2.63 (q, J=7 Hz, 2H), 7.21 (bs, 1H), 7.38-7.56 (aromatic H's, 3H), 7.79 (dd, J=8, 1.8 Hz, 2H). MS (ESI, positive ion): m/z 220.2 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[S:54]1[CH:58]=[CH:57][N:56]=[C:55]1[C:59](Cl)=[O:60]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:59]([C:55]2[S:54][CH:58]=[CH:57][N:56]=2)=[O:60])[CH2:48]1
Reactant: O=C(Cl)c1nccs1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)c2nccs2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 83 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1,3-thiazole-2-carbonyl chloride as the starting materials in 83% yield. LCMS for C27H26ClN8O2S (M+H)+: m/z=561.0.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.Cl.C(Cl)Cl.C([OH:29])C>O>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[O:29]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: CCO
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(CC(=O)O)cc1
Yield: 87 %

Procedure:
To a solution of 2-[4-(bromomethyl)phenyl]acetic acid (770 mg, 3.36 mmol) in ethanol (6 mL) and water (6 mL) was added hexamethylenetetramine (1.26 g, 9.0 mmol) and the mixture was heated to reflux for 4 hours. Concentrated HCl (1.5 mL) was added cautiously to the mixture at reflux. The mixture was heated to reflux for 30 minutes and then allowed to cool. Water (20 mL) and DCM (20 mL) were added and the organic phase was passed through a hydrophobic fit and the solvent was removed in vacuo to afford the title compound as an off-white solid (479 mg, 87%). 1H NMR (400 MHz, CDCl3): δ 10.01 (s, 1H), 7.86 (d, J=7.9 Hz, 2H), 7.47 (d, J=7.9 Hz, 2H), 3.75 (s, 2H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:10][C@@H:9]([N+:11]([O-:13])=[O:12])[C@H:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH2:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C@H:8]1[C@H:9]([N+:11]([O-:13])=[O:12])[CH2:10][C:5]([CH2:4][NH2:1])=[CH:6][CH2:7]1
Reactant: [N-]=[N+]=NCC1=CC[C@@H](c2ccc(Cl)cc2Cl)[C@H]([N+](=O)[O-])C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCC1=CC[C@@H](c2ccc(Cl)cc2Cl)[C@H]([N+](=O)[O-])C1
Temperature: 65 °C

Procedure:
To a solution of Example 12B (700 mg, 2.14 mmol) in mixture of tetrahydrofuran/H2O (15 mL/1.5 mL), triphenylphosphine (1.12 mg, 4.28 mmol) was added at room temperature. The reaction mixture was heated to 65° C. for five hours. It was cooled to room temperature, concentrated under reduced pressure, azeotroped with toluene, and purified by flash chromatography (eluting with 10% methanol/CH2Cl2) to provide the title compound. 1H NMR (500 MHz, methanol-d4) δ ppm 7.41-7.48 (m, 2H), 7.28-7.35 (m, 1H), 5.72 (m, 1H), 5.26-5.38 (m, 1H), 3.93-4.04 (m, 1H), 3.17-3.42 (m, 4H), 2.72-2.84 (m, 2H). MS (DCI) m/z 301 (M+H)+.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl[CH:11]([C:17](=[O:19])[CH3:18])[CH:12](OC)OC.C([O-])(=O)C.[Na+]>O1CCOCC1>[C:17]([C:11]1[N:8]=[C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[NH:9][CH:12]=1)(=[O:19])[CH3:18]
Reactant: CCCCCCC(=N)N
Reactant: COC(OC)C(Cl)C(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCCCc1nc(C(C)=O)c[nH]1
Reaction time: 8 h
Yield: 42 %

Procedure:
Repeating the above procedure with 0.20 mole of heptanamidine, 0.15 mole 2-chloro-1,1-dimethoxy-3-butanone, 0.35 mole sodium acetate in 400 ml dioxane by refluxing for six hours, allowing to stand overnight at room temperature and work-up as above, affords a 42% yield of pure product, M.P. 104°-106° C. and 26% of impure product. For the pure sample: 1H-NMR (CDCl3) ppm (delta): 0.85 (t, 3H), 1.28 (m, 7H), 1.75 (m, 2H), 2.52 (s, 3H), 2.83 (t, 2H), 7.72 (s, 1H).
Reaction SMILES: [C:1](#[N:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].CC([O-])(C)C.[K+]>O>[NH2:8][C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=1[C:1]#[N:9]
Reactant: N#CCCCCCC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: N#CC1=C(N)CCCC1
Temperature: 80 °C
Yield: 74.5 %

Procedure:
A stirred mixture of 1,7-heptanedinitrile (24.44 g, 0.2 mol) and t-BuOK (22.44 g, 0.2 mol) was heated at 80° C. for 3 h under nitrogen. The mixture was then cooled down to room temperature and stored at that temperature overnight. The residue was treated with water, and extracted with ether (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by recrystallization from MeOH to give the title compound as a white solid (18.2 g, 75%). 1H NMR (400 MHz, CDCl3) δ1.58-1.71 (m, 4H), 2.12-2.20 (m, 4H), 4.23 (bs, 2H). MS 123 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([F:16])[CH:3]=1.Br[CH:18]([CH3:27])[C:19]([O:25][CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:18]([CH3:27])[C:19]([O:25][CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:12]=2)=[C:4]([F:16])[CH:3]=1
Reactant: COC(=O)C=C(OC)C(C)Br
Reactant: Oc1ccc(Oc2ccc(Br)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Yield: 58.2 %

Procedure:
A mixture of 12.0 g (42.4 mmol) 4-(4-bromo-2-fluorophenoxy)phenol, 9.5 g (42.4 mmol) methyl 4-bromo-3-methoxy-2-pentenoate, 6.45 g (46.6 mmol) potassium carbonate and 180 ml acetonitrile was heated at reflux for 16 hours. The mixture was poured into water and extracted with ether. The combined ether extracts were washed with dilute aqueous NaOH, washed with water, dried over MgSO4 and the solvent was removed by rotary evaporation. The residue was purified by HPLC eluting with 95:5 hexane:acetone, to give 10.5 g (58 percent) of the product as a clear colorless oil. Calc: C, 53.66; H, 4.27. Found: C, 53.28, H, 4.40. Structure was established on the basis of IR and NMR analysis.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH:9]([C:22]1[CH:26]=[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])[O:24][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>ClCCl>[C:1]([NH:8][CH:9]([C:22]1[CH:26]=[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])[O:24][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCC(N)c1coc([Si](C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCC(NC(C)=O)c1coc([Si](C)(C)C)c1
Reaction time: 8 h

Procedure:
Acetic anhydride (0.1 ml) was added to a solution of 3-(1-aminotridecyl)-5-trimethylsilylfuran (89.8 mg, 0.27 mmol) and triethylamine (0.1 ml) in dichloromethane (1 ml) at room temperature. Stirring was continued overnight (14 hours) while the cooling bath attained room temperature. The residue, after solvent removal, was purified by preparative TLC (20×20 cm, 1000 u; developed with 60% ethyl ether/hexane). The title amide was obtained as a pale yellow oil.
Reaction SMILES: Cl.[CH3:2][NH2:3].Cl[C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=[CH:15]3)[CH:8]=[CH:7][N:6]=1.CCOC(C)=O>O>[CH3:2][NH:3][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=[CH:15]3)[CH:8]=[CH:7][N:6]=1
Reactant: CN
Reactant: O=C(O)c1cccc2cc(Oc3ccnc(Cl)c3)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1cc(Oc2ccc3c(C(=O)O)cccc3c2)ccn1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To melted methylamine hydrochloride (Aldrich, 73.7 g, 1090 mmol) at 235° C. (oil bath) was added 6-(2-chloropyridin-4-yloxy)-1-naphthoic acid (6.54 g, 21.8 mmol). The reaction mixture was stirred for 3 min and cooled to RT. The brownish solid was treated with EtOAc and water and stirred until all residue was either in solution or suspended. The precipitate was filtered off, washed with EtOAC and purified by silica gel chromatography using 0-100% of a 85:15:0.5 mixture of DCM:MeOH:AcOH. The product obtained was washed with water, filtered and dried under vacuum to give the title compound.
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20]([C:35]#[N:36])[N:19]=3)=[CH:13][C:12]=2[F:37])[CH:7]=[CH:6][N:5]=1)(=O)N.[ClH:38].[NH2:39]C1C=C(OC2C=CC(NC3N=CC=CC=3C(NC3C=CC(F)=CC=3F)=O)=CC=2F)C=CN=1>>[ClH:38].[ClH:38].[NH2:39][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20]([C:35]#[N:36])[N:19]=3)=[CH:13][C:12]=2[F:37])[CH:7]=[CH:6][N:5]=1
Reactant: N#Cc1ncc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)n1
Reactant: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Agent: Cl
Product: N#Cc1ncc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc(N)c3)c(F)c2)n1
Yield: 53 %

Procedure:
4-(4-(2-Carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-2-cyano-N-(2,4-difluorophenyl)pyrimidine-5-carboxamide (171 mg, 0.33 mmol) was converted to the title compound (90 mg, 53%) in a manner similar to the preparation of 2-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide (Step E of Example 3). 1H NMR (DMSO-d6) δ 10.85 (s, 1H), 10.83 (s, 1H), 9.11 (s, 1H), 7.99 (m, 2H), 7.83 (br s, 2H), 7.68-7.40 (m, 4H), 7.20 (m, 1H), 6.75 (dd, 1H, J=7.3, 2.4 Hz), 6.20 (d, 1H, J=2.4 Hz); MS(ESI+) m/z 478 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:15][C:16]([CH3:32])([CH2:19][N:20]1[CH:28]=[C:27]2[C:22]([C:23]([Cl:31])=[C:24]([Cl:30])[CH:25]=[C:26]2[Cl:29])=[N:21]1)[C:17]#[N:18]>C1COCC1>[C:17]([C:16]([NH:15][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:2]=1[F:1])([CH3:32])[CH2:19][N:20]1[CH:28]=[C:27]2[C:22]([C:23]([Cl:31])=[C:24]([Cl:30])[CH:25]=[C:26]2[Cl:29])=[N:21]1)#[N:18]
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C(F)(F)F)cc1F

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 2-fluoro-4-trifluoromethylbenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=493, RT=0.75 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][P:29](=[O:36])([O:33]CC)[O:30]CC)=[CH:26][C:4]=2[N:3]=1.C[Si](Br)(C)C>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][P:29](=[O:30])([OH:33])[OH:36])=[CH:26][C:4]=2[N:3]=1
Reactant: CCOP(=O)(CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: COc1ccc(CCc2cnc3c(N)nc4cc(CCP(=O)(O)O)ccc4c3c2)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)ethylphosphonate (3-3) (1.0 equiv.) in DCM (0.02 M) at 0° C. was added TMSBr (10 equiv.). The reaction was warmed to room temperature over 2 hours, and then quenched with small amounts of MeOH. The DCM was removed by evaporation, and then DMSO/water was added. The mixture was adjusted to pH 9 and directly purified on RP-HPLC using a C18 column, eluting with 10-40% 95:5 (MeCN/5 mM NH4OAc) in 10 mM NH4OAc (pH 9) gradient. The fractions containing the product were combined and concentrated in vacuo to give 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)ethylphosphonic acid (11) as a solid. 1H NMR (Dimethylsulfoxide-d6): δ 9.66 (s, 1H), 9.30 (s, 1H), 8.95 (s, 1H), 8.78 (s, 1H), 8.50 (d, 1H, J=8.4 Hz), 7.54 (s, 1H), 7.45 (d, 1H, J=8.4 Hz), 7.02 (d, 1H, J=8.4 Hz), 6.69 (d, 1H, J=2.8 Hz), 6.61 (dd, 1H, J=2.8, 8.4 Hz), 3.64 (s, 3H), 3.14-3.06 (m, 2H), 3.00-2.90 (m, 4H), 2.22 (s, 3H), 2.02-1.92 (m, 2H). LRMS [M+H]=452.2
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]1([C:12]([OH:14])=[O:13])[CH2:11][CH:10]=[CH:9][CH2:8]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH:7]1([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:11][CH:10]=[CH:9][CH2:8]1
Reactant: O=C(O)C1CC=CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)C1CC=CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.6 %

Procedure:
K2CO3 (35.0 g, 255 mmol) was added to a solution of cyclopent-3-enecarboxylic acid (20.0 g, 178 mmol) in acetonitrile (500 mL) followed by addition of benzyl bromide (36.6 g, 214 mmol). The reaction mixture was stirred for 12 h at ambient temperature. The mixture was filtered and washed with acetonitrile (200 mL). The filtrate and washings were combined and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc=10:1) to afford benzyl cyclopent-3-enecarboxylate (26.5 g, 74% yield) as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:25])[C:17]3[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=3)[C:22]#[N:23])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C>>[OH:31][C:5]1[C:6]([CH2:28][CH2:29][CH3:30])=[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([OH:25])[C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:22]4[N:32]=[N:33][NH:34][N:23]=4)[CH:24]=3)=[CH:14][CH:15]=2)[CH:26]=[CH:27][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(O)c3cncc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCc1c(OCc2ccc(C(O)c3cncc(-c4nn[nH]n4)c3)cc2)ccc(C(C)=O)c1O
Yield: 32.5 %

Procedure:
Using the general procedure of Example 1 using 5-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-nicotinonitrile (473 mg, 1.14 mmol), sodium azide (738 mg, 11.4 mmol), and triethylamine hydrochloride (1.56 g, 11.4 mmol) to yield the title product as a white solid (170 mg, 33%): 1H NMR (DMSO-d6) δ 0.85 (t, 3H), 1.35 (s, 1H), 1.47 (sextet, 2H), 2.56 (m, 5H), 5.22 (bs, 2H), 5.93 (d, 1H), 6.29 (d, 1H), 6.71 (d, 1H), 7.45 (q, 4H), 7.78 (d, 1H), 8.39 (t, 1H), 8.77 (d, 1H), 9.07 (d, 1H), 12.83 (s, 1H); MS (esi negative) m/z (rel intensity) 458 (100).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15]3)[CH2:10]2)[CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@@H:16]12[N:9]([C:5]3[CH:4]=[C:3]([N:2]([CH3:24])[CH3:1])[CH:8]=[CH:7][N:6]=3)[CH2:10][C@@H:11]1[CH2:12][CH2:13][NH:14][CH2:15]2
Reactant: CN(C)c1ccnc(N2C[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]32)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccnc(N2C[C@@H]3CCNC[C@@H]32)c1
Temperature: 25 °C

Procedure:
A solution of (1R,6S)-tert-butyl 8-(4-(dimethylamino)pyridin-2-yl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (150 mg, 0.45 mmol) in DCM (5 mL) was added TFA (2 mL). The resulting mixture was allowed to stir at ambient temperature. After 16 hours the crude mixture was concentrated under reduced pressure. The resulting trifluoroacetic acid salt of the title compound was used without further purification. MS (ESI) mass calcd. for C13H20N4, 232.2; m/z found, 233.2 [M+H]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH:6]1[CH:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[CH:8]([C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7]1.[O:22]1CCOCC1.[ClH:28]>>[ClH:28].[CH:20]1[C:21]2[CH:8]3[CH2:7][CH:6]([C:2]([O:1][CH2:5][CH2:4][NH2:3])=[O:22])[CH:15]([C:14]4[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C1COCCO1
Reactant: c1ccc2c(c1)C1CC(C3=NCCO3)C2c2ccccc21
Agent: Cl
Product: NCCOC(=O)C1CC2c3ccccc3C1c1ccccc12
Reaction time: 2.5 h

Procedure:
A solution of 11-(2-oxazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene (4.122 g) in 1.074 N hydrochloric acid (13.9 ml) is allowed to stand at room temperature for 2.5 hours. The reaction mixture is mixed with dioxane to dissolve the precipitate formed and evaporated at room temperature under reduced pressure to remove the solvent. The residue is recrystallized from anhydrous ethanol-ether to give 2-aminoethyl 9,10-dihydro-9,10-ethanoanthracene-11-carboxylate hydrochloride 1/2 hydrate (4.641 g) as crystals melting at 155 to 158° C. IR (Nujol), 3379, 1735 cm-1.