Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:14]O>OS(O)(=O)=O>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cnc(N)c([N+](=O)[O-])c1
Yield: 30 %

Procedure:
A solution of 6-Amino-5-nitro-nicotinic acid (2) (15.2 g, 82.5 mmol) in MeOH (250 ml) and H2SO4 (conc. 25 ml) was heated at reflux for 5 h. The solution was concentrated in vacuo and the residue treated with saturated aqueous NaHCO3 solution until slightly basic. The resulting solid was collected by filtration, rinsed with H2O and dried in vacuo to give the product as a yellow solid (4.8 g, 25 mmol, 30%) that was used as is without further purification. TLC of the solid in DCM/MeOH (19:1) showed a less polar compound at Rf=0.5 compared to the baseline starting material.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].[F:10][C:11]([F:17])([F:16])[CH2:12][N:13]=[C:14]=[O:15].C1COCC1>C1C=CC=CC=1>[F:10][C:11]([F:17])([F:16])[CH2:12][NH:13][C:14]([NH:2][NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:15]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C=NCC(F)(F)F
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)NNC(=O)NCC(F)(F)F
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
To a stirred solution of tert-butyl hydrazinecarboxylate (1.0 g, 8 mmol) in anhydrous benzene (10.0 mL) was added 1,1,1-trifluoro-2-isocyanatoethane (1.06 g, 8 mmol) neat via syringe to give a gelatin like mixture. Anhydrous THF was added to give a clear solution which was stirred for 10 minutes, after which time the reaction mixture was evaporated to afford the title compound as a white solid (1.62 g, 79%): 1H NMR (400 MHz, CDCl3) δ 6.63 (s, 1H), 6.40 (d, J=2.2 Hz, 1H), 5.84 (s, 1H), 3.88 (qd, J=9.0, 6.6 Hz, 2H), 1.48 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −73.20. This material is used without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([Br:18])[CH:8]=[CH:9][C:10]=2[NH:14][C:15](=[O:17])[CH3:16])[CH2:5]1)(=[O:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([Br:18])[CH:8]=[C:9]([N+:19]([O-:21])=[O:20])[C:10]=2[NH:14][C:15](=[O:17])[CH3:16])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Br)c2c1CCN(C(C)=O)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1c([N+](=O)[O-])cc(Br)c2c1CCN(C(C)=O)C2
Temperature: 25 °C

Procedure:
The product from Example 21 (31 g) was dissolved in trifluoroacetic acid (450 mL). The solution was treated dropwise with 33 mL of fuming 90% nitric acid and stirred at room temperature. The reaction mixture was concentrated, the residue was dissolved in chloroform and then washed well with sodium bicarbonate solution. A solid formed, and was dissolved in 3 L chloroform and dried over magnesium sulfate. After evaporation, the residue was crystallized from ethyl acetate to give a white solid (19.32 g), and the filtrate concentrated to give an additional 16.3 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.Cl.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[OH:32][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:3][CH:4]=2)[C:13]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=2[O:11][CH2:10][CH:9]1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=1
Reactant: ClCCN1CCCCC1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Yield: 7 %

Procedure:
4-(4-Hydroxyphenyl)-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (310 mg, 0.59 mmol) prepared in Example 15, [1-(2-chloroethyl)]piperidine.HCl (176 mg, 0.9 mmol) and K2CO3 (264 mg, 1.8 mmol) were dissolved in acetone (8 ml) and then refluxed for 62 hours. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer thus separated was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The residue was separated by column chromatography (n-hexane:ethyl acetate=1:2) to obtain 83 mg (yield: 7%) of the title compound as a white foam.
Reaction SMILES: [CH:1]1([C:4]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)=[CH2:5])[CH2:3][CH2:2]1>O.[Ru](=O)=O.C(O)(C)C>[CH:1]1([CH:4]([CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][CH2:11]2)[CH3:5])[CH2:3][CH2:2]1
Reactant: C=C(C1CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Ru]=O
Solvent: CC(C)O
Solvent: O
Product: CC(C1CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 92.8 %

Procedure:
Add ruthenium dioxide monohydrate (2.0 g, 15.0 mmol) to a 500 mL Parr shaker bottle and wet with isopropyl alcohol (25 mL). Add tert-butyl 4-(1-cyclopropylethenyl)piperidine-1-carboxylate (3.8 g, 15.1 mmol) and isopropyl alcohol (100 mL) and place on Parr shaker. React under H2 atmosphere (30 psi) at ambient temperature for a total of 12 hours. Vent and purge the bottle, filter and concentrate in vacuo to give the title compound as a clear oil (3.55 g, 92.9%). MS (m/z): 198 (M+1-tBu)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:26])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[C:22](OC)=[O:23])[CH:5]=[CH:6][C:7]=1[CH3:8].[BH4-].[Li+].C1COCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:26])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH2:22][OH:23])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1c(N(C)c2ccc(C)c(C)c2)c2ccccc2c(=O)n1C
Agent: [BH4-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(N(C)c2c(CO)n(C)c(=O)c3ccccc23)cc1C
Temperature: 70 °C
Reaction time: 6 h
Yield: 48.4 %

Procedure:
To a stirred solution of methyl 4-[(3,4-dimethylphenyl)(methyl)amino]-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (2.11 g, 6.02 mmol) in toluene (12 mL) was added dropwise 2 M lithium borohydride/THF (3.06 mL, 6.11 mmol). The mixture was stirred at 70° C. for 6 hours, quenched with 1M HCl/water and partitioned between EtOAc and aq. NaHCO3. The organic phase was dried over sodium sulfate, evaporated in vacuo and purified on silica using EtOAc/hexanes 20-50% to provide the title compound as an off-white solid (0.94 g, 48%). 1H NMR (400 MHz, CDCl3) δ ppm 8.51 (br. s., 1 H), 7.57 (br. s., 2 H), 6.96 (br. s., 1 H), 6.44 (br. s., 2 H), 4.80-4.48 (m, 2 H), 3.80 (br. s., 3 H), 3.27 (br. s., 3 H), 2.16 (d, 11 H), 2.29-2.06 (m, 6 H); ES-LCMS: 323.4 (M+1); ES-LCMS: 323.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[C:31]([N:33]2[C:38](=[O:39])[NH:37][C:36](=[O:40])[C:35]([C:41]#[N:42])=[N:34]2)[CH:30]=[C:29]([Cl:43])[C:3]=1[O:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:14])[N:7]([CH2:15][O:16][P:17](=[O:28])([O:23]C(C)(C)C)[O:18]C(C)(C)C)[N:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:32]=[C:31]([N:33]2[C:38](=[O:39])[NH:37][C:36](=[O:40])[C:35]([C:41]#[N:42])=[N:34]2)[CH:30]=[C:29]([Cl:43])[C:3]=1[O:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:12])[CH3:13])[C:8](=[O:14])[N:7]([CH2:15][O:16][P:17](=[O:18])([OH:28])[OH:23])[N:6]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(COP(=O)(O)O)c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
A solution of phosphoric acid di-tert-butyl ester 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester (44.0 mg, 0.067 mmol) in methylene chloride (1.0 mL, 0.067M) at 25° C. was treated with trifluoroacetic acid (0.2 mL). The reaction mixture was stirred at 25° C. for 20 min. At this time, the reaction mixture was concentrated in vacuo, azeotropically dried with benzene and concentrated from absolute ethanol followed by lyophilization from acetonitrile and water to afford phosphoric acid mono-{3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl}ester (31.4 mg, 86%) an off-white solid. Present in the product was 0.95 moles of residual ammonium from the ammonium acetate used in the supercritical fluid purification of the precursor. ES+-HRMS m/e calcd for C18H15N6O8PCl2 (M+Na+) 566.9958, found 566.9962.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN1C(=O)N(C)CCC1.I[C:38]1[C:51](I)=[CH:50][C:49]2[C:40](=[C:41]([CH2:56][CH2:57][CH3:58])[C:42]3[C:47]([C:48]=2[CH2:53][CH2:54][CH3:55])=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:39]=1>C1COCC1.Cl[Cu]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:44]3[C:45](=[CH:46][C:47]4[C:42]([CH:43]=3)=[C:41]([CH2:56][CH2:57][CH3:58])[C:40]3[C:49](=[CH:50][CH:51]=[CH:38][CH:39]=3)[C:48]=4[CH2:53][CH2:54][CH3:55])[C:15]([C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=3)=[C:14]3[C:9]=2[CH2:10][CH2:11][CH2:12][CH2:13]3)=[CH:6][CH:7]=1
Reactant: Brc1ccc(C#CCCCCC#Cc2ccc(Br)cc2)cc1
Reactant: CCCc1c2ccccc2c(CCC)c2cc(I)c(I)cc12
Agent: Cl[Cu]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCCc1c2ccccc2c(CCC)c2cc3c(-c4ccc(Br)cc4)c4c(c(-c5ccc(Br)cc5)c3cc12)CCCC4
Temperature: 50 °C
Yield: 57 %

Procedure:
1,8-Bis(p-bromophenyl)-1,7-octadiyne (0.191 g, 0.459 mmol) was added at −78° C. to a THF solution of bis(η5-cyclopentadienyl)dibutylzirconium in THF, which was prepared from bis(η5-cyclopentadienyl)dichlorozirconium (0.161 g, 0.551 mmol) and n-butyl lithium (0.7 ml, 1.6 M, 1.1 mol/l). The mixture was then allowed to stand at room temperature for an hour. CuCl (0.095 g, 0.964 mmol), DMPU (0.17 ml, 1.38 mmol) and 2,3-diiodo-9,10-dipropylanthracene (0.236 g, 0.459 mmol) were added to the mixture. After heating at 50° C. for an hour, the solvent in the mixture was removed in vacuum. Column chromatography (chloroform) was performed. By recrystallization in chloroform/methanol, the title compound (0.177 g) was obtained as orange red. The isolation yield was 57%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])CCC.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>O1CCCC1.CCCCCC>[S:1]1[C:5]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][Br:15])=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: BrCCCCCCBr
Reactant: c1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: BrCCCCCCc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of benzo[b]thiophene (1.92 g., 14.3 mmol) in 90 ml anhydrous tetrahydrofuran at -10° to 0° under argon was added n-butyllithium (7.8 ml of a 1.86M solution in hexane). After two hours, this solution was transferred dropwise into a stirred, 0° solution of 1,6-dibromohexane (6.5 ml, 0.043 mol) in 250 ml tetrahydrofuran. The solution was warmed to room temperature, stirred for 15 hours, quenched with water and concentrated. The residue was acidified and partitioned between ethyl ether and water. The aqueous portion was extracted twice with ether, and the combined organic portions were washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a brown oil. Excess benzo[b]thiophene and 1,6-dibromohexane were removed by bulb to bulb distillation (85° to 90°/0.1 mm) to leave a dark brown syrup. This material was purified by flash chromatography (silica, hexane to 5% ethyl ether/hexane) to give the desired alkyl halide.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][S:14]([CH3:13])(=[O:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCc1ccccc1
Yield: 102.4 %

Procedure:
Operating analogously to example 19 using 5-phenylpentanol (7.18 ml, 7 g, 42.6 mmoles) in methylene chloride (8 ml) and methyl-sulfonyl chloride (3.63 ml, 5.37 g, 46.9 mmoles) in methylene chloride (4 ml), and also using triethylamine (6.82 ml, 4.96 g, 49 mmoles) to adjust the pH after the addition of methyl-sulfonyl chloride, 10.57 g of the title product were obtained after half an hour of reaction (stoichiometric yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:15][C@H:14]2[C@@H:5]([C@@H:6]3[C@@H:11]([CH2:12][CH2:13]2)[CH2:10][C@@:9]2([CH3:20])[CH2:16][C:17](=[O:19])[CH2:18][C@@H:8]2[CH2:7]3)[CH2:4][CH2:3]1.[I-].[CH3:22][S+](C)C.CC(C)([O-])C.[K+].O>CS(C)=O>[CH3:20][C@:9]12[C@@:16]3([CH2:17][O:19]3)[CH2:22][CH2:18][C@@H:8]1[CH2:7][C@H:6]1[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:5]1[CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:15]3)[CH2:10]2
Reactant: C[S+](C)C
Reactant: C[C@]12CC(=O)C[C@@H]1C[C@H]1[C@@H](CC[C@H]3C[C@H](O)CC[C@@H]31)C2
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@]12C[C@@H]3CC[C@H]4C[C@H](O)CC[C@@H]4[C@H]3C[C@H]1CC[C@]21CO1
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a solution of compound 45 (45 mg, 0.16 mmol) in DMSO (3 mL) was added trimethylsulfonium iodide (202 mg, 1.0 mmol) and potassium tert-butoxide (112 mg, 1.0 mmol) at room temperature. After 3 h, water was added (20 mL) and the product extracted into EtOAc (50 mL×3). The combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexanes) to give compound 46 (35 mg, 75%) as a white solid: mp 165-167° C.; [α]D25 +20.0 (c 0.12, CHCl3); 1H NMR (CDCl3) δ 4.08 (s, 1H), 2.90 (d, J=15.2 Hz, 1H), 2.60 (d, J=15.2 Hz, 1H), 0.87 (s, 3H); 13C NMR (CDCl3) δ 70.5, 66.5, 53.6, 48.3, 47.2, 47.0, 42.1, 40.4, 40.2, 37.9, 36.2, 34.2, 34.0, 32.8, 29.0, 28.8, 25.8, 23.3, 14.3; IR νmax 3418, 1443, 1378, 851 cm−1. MS (FAB) for [C19H30O2]+: 290.2246. Found: 290.2243.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][C@H:4]([OH:26])[C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C@@H:17]([CH3:20])[CH2:18][CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:34][C@@H:35]([CH2:54][CH3:55])[C@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[N:47]=2)[C:41]1=[O:53])[C:37](O)=[O:38].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[CH:17]([CH3:20])[CH2:18][CH3:19])=[O:15])[C@@H:4]([OH:26])[CH2:3][C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[N:47]=2)[C:41]1=[O:53])[CH:35]([CH3:34])[CH2:54][CH3:55])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C)n2)C1=O
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccccc1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)CC)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
A solution containing the product from Example 9B (0.36 g, 0.79 mmol) in THF (8 mL) was treated with the product from Example 7B (0.33 g, 0.79 mmol), DEPBT (0.355 g, 1.19 mmol), and N,N-diisopropylethylamine (0.70 mL, 4.02 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-50% acetone/dichloromethane to give the title compound (0.264 g, 45% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.75 (m, 12 H), 0.94 (m, 2 H), 1.29 (m, 2 H), 1.46 (m, 2 H), 1.62 (m, 1 H), 1.80 (m, 1 H), 2.43 (m, 4 H), 2.68 (m, 3 H), 2.88 (m, 1 H), 3.08 (m, 3 H), 3.56 (m, 4 H), 3.84 (m, 2 H), 4.15 (m, 2 H), 4.34 (s, 2 H), 4.84 (d, J=5.88 Hz, 1 H), 7.03 (m, 7 H), 7.15 (m, 6 H), 7.39 (d, J=9.19 Hz, 1 H), 7.66 (t, J=7.72 Hz, 1 H), 7.83 (d, J=8.82 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[K+].OO.O.CC[O:29]C(C)=O>CCO.O>[F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[NH:14][CH:15]=[C:16]([C:18]([NH2:19])=[O:29])[N:17]=3)=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1c[nH]c(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: CCOC(C)=O
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)c1c[nH]c(-c2ccc(Oc3ccc(F)cc3)cc2)n1

Procedure:
To a solution of 0.56 g (6.83 mmol) of sodium acetate in 10 mL of water was added 1.29 g (4.78 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone. The resulting solution was warmed for 30 minutes and then cooled in an ice/water bath. A solution of 4-(fluorophenoxy)benzaldehyde (789 mg, 3.65 mmol) in MeOH was added, followed by 10 mL of a concentrated aqueous NH4OH solution. Additional MeOH was added until a homogenous solution formed. After stirring at room temperature overnight, the reaction was diluted with water. The precipitate that formed was collected, washed with water and dried. Column chromatography (gradient from 8/2 to 2/3 hexane/EtOAc) afforded 0.6 g of a solid. A mixture of 0.5 g of the solid and 80 mL of a concentrated aqueous NH4OH solution was diluted with MeOH until a solution formed. The reaction was heated in a sealed tube for 1.5 days. After cooling to room temperature, the mixture was added to a water/EtOAc mixture. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, dried (Na2SO4), filtered and concentrated to dryness. Column chromatography (1:1 hexane/EtOAc) gave 2-[4-(4-fluorophenoxy)phenyl]-1H-imidazole-4-carbonitrile as a solid. 1H NMR (DMSO-d6): δ13.37 (br s, 1H), 8.23 (s, 1H), 7.95 (d, 2H, J=8.7 Hz), 7.27 (t, 2H, J=8.9 Hz), 7.15 (dd, 2H, J=9.3, 4.5 Hz), 7.08 (d, 2H, J=8.7 Hz). To a solution of the nitrile in EtOH was added 1 g of KOH dissolved in 5 mL of water and 1.5 mL of a 30% aq. H2O2 solution. After heating at reflux for 3 hours, the reaction was added to water/EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo. The residue was subjected to flash chromatography (100% EtOAc) affording the title compound as a white solid, TLC Rf 0.34 (5% MeOH/EtOAc). 1H NMR (CDCl3): δ12.90 (br s, 1H), 8.08 (br s, 1H), 7.97 (d, 2H, J=9.0 Hz), 7.70 (s, 1H), 7.63 (br s, 1H), 7.26 (t, 2H, J=8.7 Hz), 7.15-7.10 (m, 2H), 7.07 (d, 2H, J=8.7 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[C:26]([F:28])[CH:27]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[CH:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][N:7]=[C:4]2[CH2:3][CH2:2][N:1]([C:25]3[C:26]([F:28])=[CH:27][C:22]([Br:21])=[CH:23][N:24]=3)[CH2:6][CH2:5]2)[CH2:14][CH2:13]1)=[O:16])([CH3:20])[CH3:19]
Reactant: Fc1cc(Br)cnc1Cl
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc(Br)cc3F)CC2)CC1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
2d (0.22 g, 0.71 mmol), 3-bromo-6-chloro-5-fluoro-pyridine (0.2 g, 0.95 mmol) and diisopropylethylamine (0.2 mL, 1.2 mmol) in 2 mL of DMSO were heated at 130° C. for 20 h. The mixture was cooled to room temperature and purified by flash LC(0 to 30% EtOAc+0.1% triethylamine in hexane) to afford 46a (92 mg, 28% yield): HPLC, LC-MS 457.1 (MH).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH2:2][CH3:3].Cl[C:12]1[N:13]=[N+:14]([O-:25])[C:15]2[CH:24]=[C:23]3[C:19]([CH2:20][CH2:21][CH2:22]3)=[CH:18][C:16]=2[N:17]=1>COCCOC>[O-:25][N+:14]1[C:15]2[CH:24]=[C:23]3[C:19](=[CH:18][C:16]=2[N:17]=[C:12]([NH:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][CH3:10])[CH2:1][CH2:2][CH3:3])[N:13]=1)[CH2:20][CH2:21][CH2:22]3
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: CCCN(CCC)CCN
Solvent: COCCOC
Product: CCCN(CCC)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Yield: 75.9 %

Procedure:
N1,N1-Dipropyl-1,2-ethanediamine (297) (0.27 g, 1.9 mmol) was added to a stirred solution of chloride 21 (298 mg, 1.3 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 28 (325 mg, 74%) as a yellow powder: mp (MeOH/EtOAc) 95-97° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.80 (br s, 1H, NH), 3.46-3.53 (m, 2H, CH2N), 2.96-3.03 (m, 4H, 2×CH2N), 2.68 (dd, J=6.0, 5.8 Hz, 2H, CH2N), 2.38-2.45 (m, 4H, H-6, H-8), 2.10-2.18 (m, 2H, H-7), 1.41-1.51 (m, 4H, 2×CH2), 0.87 (t, J=7.1 Hz, 6H, 2×CH3); 13C NMR δ 158.7, 154.4, 148.8, 143.0, 129.8, 120.5, 114.7, 55.9 (2), 52.6, 38.9, 31.1, 32.3, 25.7, 20.3 (2), 11.9 (2). Anal. calcd for C18H27N5O: C, 65.6; H, 8.3; N, 21.3. Found: C, 65.4; H, 8.4; N, 21.3%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[F:31][C:32]([F:42])([F:41])[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[C:33]([C:32]([F:31])([F:41])[F:42])[CH:34]=2)[CH:6]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.40 g, 0.001 mol) in DMF (10 mL), was added 3-trifluoromethylbenzyl bromide (0.24 g, 0.001 mol) and powdered potassium carbonate (0.96 g, 0.007 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.43 g in 77% yield. 1H NMR (CDCl3) δ 7.40 (d, 1H), 7.37 (s, 1H), 7.24 (m, 7H), 7.19 (m, 6H), 6.83 (d, 1H), 6.62 (s, 1H), 6.59 (dd, 1H), 4.16 (t, 1H), 3.67 (s, 3H), 3.63 (s, 2H), 3.58 (t, 2H), 3.55 (s, 2H), 3.08 (d, 2H), 2.61 (t, 2H), 1.79 (t, 2H); 13C NMR (CDCl3) δ 173.4, 160.4, 144.7, 143.7, 142.2, 136.6, 133.8, 133.5, 131.9, 130.8, 130.2, 129.9, 129.8, 127.8, 126.8, 125.1, 125.0, 122.7, 116.8, 115.7, 114.5, 66.8, 61.1, 60.2, 53.5, 51.8, 42.6, 28.2.