Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N2C=NC3C2=NC(OCC)=NC=3N)CCCC=C1.[CH:20]1([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][C:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[N:30][C:31]=3[NH2:35])[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1>>[CH2:37]([O:36][C:29]1[N:28]=[C:27]2[C:32]([N:33]=[CH:34][N:26]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:31]([NH2:35])[N:30]=1)[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Agent: CCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Product: CCCCCCOc1nc(N)c2ncn(C3CCCCC3)c2n1
Yield: 90 %

Procedure:
The procedure of Example 8 was repeated except that the 9-(2-cyclohexenyl)-2-ethoxy-9H-adenine used therein was replaced by an equivalent weight of 9-(2-cyclohexenyl)-2-n-hexyloxy-9H-adenine. There was produced the title product in 90% yield: m.p. 57°-60° C. IR(neat): 3500, 1635, 1595, 1500, 1465, 1420, 1400 cm-1. UV: λmaxEtOH 253 nm(ε7200), 270 nm(ε10900). NMR(CDCl3): 1.5(21H, m), 4.25(2H, t, J=6.5 Hz), 4.40(1H, m), 6.07(2H, s), 7.54(1H, s).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH2:8].Br[CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].[I-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][NH:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH:8][CH2:23][N:24]1[C:25](=[O:34])[C:26]2=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]2[C:28]1=[O:29]
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(C)C
Reactant: O=C1c2ccccc2C(=O)N1CBr
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.8 %

Procedure:
A solution of L-leucyl-L-phenylalanine N-methylamide (1.3 g) in dichloromethane (13 ml) was treated with N-bromomethylphthalimide (1.17 g) and sodium iodide (0.06 g). The resulting yellow solution was stirred at room temperature for 16 h. The solution was treated with saturated sodium bicarbonate solution (ca. 8 ml) and extracted with dichloromethane. The crude, organic extracts were preadsorbed onto silica gel and purified by flash silica chromatography, eluting with ethyl acetate/heptane (5:1), to furnish the title compound as a white solid (0.74 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28]>>[CH2:26]([S:29]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:31])=[O:30])[CH2:27][CH3:28]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CCCS(=O)(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.5 g (1.4 mmol) of material from Example 50 and 9.0 mL (0.11 mmol) 1-propanesulfonyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[CH3:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:40]=2)[NH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:39]3[CH:40]=[C:41]4[C:36](=[CH:37][CH:38]=3)[NH:35][CH:34]=[C:33]4[CH3:32])[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: Cc1c[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1c[nH]c2ccc(-c3nn(C(C)c4oc5ccccc5c(=O)c4-c4cccc(F)c4)c4ncnc(N)c34)cc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 10 %

Procedure:
To a solution of Example 57c (0.400 g, 0.757 mmoles) in DMF (5 ml), ethanol (2.5 ml) and water (2.5 ml), 3-methyl-5-indoleboronic acid pinacol ester (0.292 g, 1.136 mmoles) and sodium carbonate (0.240 g, 2.272 mmoles) were added and the system is degassed for 30 min Tetrakistriphenylphosphine Palladium (0.043 g, 0.037 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as brown solid (0.040 g, 13% yield). MP: 171-173° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 10.96(s,1H), 8.06(s,1H), 8.04(dd, J=7.9,1.4Hz, 1H), 7.85(m,1H), 7.68(d, J=8.1Hz, 2H), 7.52(d, J=7.2Hz, 1H), 7.49(d, J=8.3Hz, 1H), 7.32(dd, J=8.2,1.4Hz, 2H), 7.20(s, 1H), 7.08(dt, J=11.2,2.7Hz, 1H), 6.93(br s,2H), 6.04(q, J=7.0Hz, 1H),2.28(s,3H), 1.92(d, J=7.0Hz, 3H). Mass: 530.98(M+).
Reaction SMILES: Br[C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1.[F:35][C:36]1([F:40])[CH2:39][NH:38][CH2:37]1>>[F:35][C:36]1([F:40])[CH2:39][N:38]([C:2]2[CH:34]=[CH:33][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=5)[CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=2)[CH2:37]1
Reactant: FC1(F)CNC1
Reactant: Cn1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)n1
Product: Cn1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(N5CC(F)(F)C5)cc4)c3c2)n1

Procedure:
The title compound was prepared from racemic cis-2-(1-(4-bromobenzyl)-6-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid using analogous conditions to Example 152 using 3,3-difluoroazetidine. MS (ESI): mass calcd. for C29H31F2N5O3, 535.24; m/z found, 536.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.52 (d, J=9.6, 2H), 7.04 (d, J=8.2, 2H), 6.96 (s, 1H), 6.91 (d, J=8.8, 1H), 6.52 (d, J=8.3, 2H), 6.26 (s, 1H), 5.44 (d, J=16.5, 1H), 5.38 (d, J=16.4, 1H), 4.99 (s, 2H), 4.17 (t, J=11.9, 4H), 3.83 (s, 3H), 3.59-3.53 (m, 1H), 2.88-2.78 (m, 1H), 2.41-2.29 (m, 1H), 1.98 (s, 1H), 1.79 (t, J=27.9, 5H), 1.53-1.38 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[CH:20]1([C:25](=O)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1.[O-]CC.[Na+].C(O)C>CN(C)C=O.O1CCCC1.O>[CH:20]1([C:25]2[O:6][N:5]=[C:4]([C:3]3[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:11])[C:26]=2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)CC(=O)C1CCCC1
Reactant: ON=Cc1c(Cl)cccc1Cl
Agent: CC[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of 2,6-dichlorobenzaldehyde oxime (3.73 g, 19.6 mmol) in N,N-dimethylformamide (12 mL) was added solid N-chlorosuccinimide (2.62 g, 19.6 mmol). The solution was stirred for approximately 1 hour and the poured into water and extracted twice with ether. The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate and concentrated. To a solution of ethyl 3-cyclopentyl-3-oxopropanoate (4.34 g, 23.6 mmol) in tetrahydrofuran (5 mL) at 0° C. was added a 25 wt % solution of sodium ethoxide in ethanol (7.4 mL, 24 mmol) quickly. The above imidoyl chloride was added. A solid was seen to precipitate. The mixture was allowed to warm to ambient temperature and stir overnight. The mixture was then poured into water and extracted three times with ethyl acetate and the combined organic layers were dried over magnesium sulfate, concentrated and the residue purified by chromatography (silica gel 5% ethyl acetate in hexanes) to afford ethyl 5-cyclopentyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (3.04 g, 43%). 1H-NMR (400 MHz, DMSO-d6) δ 7.63-7.53 (m, 3H), 4.02 (q, J=7 Hz, 2H), 3.92-3.84 (m, 1H), 2.14-2.06 (m, 2H), 1.84-1.64 (m, 6H), 0.91 (t, J=5 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[O:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])([CH3:11])([CH3:10])[CH3:9]>ClCCl>[C:8]([C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[O:15][CH2:16][C:17]([OH:19])=[O:18])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)COc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(OCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 1 h
Yield: 70 %

Procedure:
3.6 ml (46 mmol) of trifluoroacetic acid is added to a solution of 1.56 g (4.64 mmol) of tert-butyl 2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]acetate (prepared according to J. Heterocycl. Chem. (1994) 31, 1439-1443) in 20 ml of dichloromethane. The reaction mixture is agitated for 1 hour, concentrated under vacuum and the residue is dissolved in 50 ml of Et2O. The organic solution is extracted twice with 25 ml of a saturated solution of NaHCO3, the aqueous phase is then washed with 25 ml of Et2O. The basic aqueous solution is then acidified, at 0° C., with a saturated solution of KHSO4 and finally the expected product is extracted using twice 25 ml of Et2O. The organic solution is dried over sodium sulphate, filtered and concentrated under vacuum in order to produce a white powder with a yield of 70%. Melting point: 172-173° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22].CCN(C(C)C)C(C)C>C1COCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:9]3[CH:10]=[CH:11][C:2]([F:1])=[C:3]([CH:8]=3)[C:4]([O:6][CH3:7])=[O:5])=[O:36])=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCNc1ccc(F)c(C(=O)OC)c1
Reactant: CCCCc1ccc(C#Cc2ccc(C(=O)Cl)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCCCN(C(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(F)c(C(=O)OC)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 128 %

Procedure:
To a solution of methyl 2-fluoro-5-(hexylamino)benzoate (185 mg; 0.73 mmol) in THF (15 mL) were added 4-[(4-butylphenyl)ethynyl]benzoyl chloride (260 mg; 0.88 mmol), DIEA (0.15 mL; 0.88 mmol) and DMAP (20 mg). The mixture was stirred at 60° C. under N2 atmosphere for 1 hour. It was then diluted with DCM (100 mL), washed with HCl 0.1N (50 mL) and a saturated solution of NaHCO3 (100 mL). The organic layer was dried over magnesium sulfate, filtrated and the solvent was removed under reduced pressure to give 480 mg of a brown solid. Purification by flash chromatography on silicagel (c-Hex/EtOAc, 90:10) gave 170 mg (45.3%) of the title compound as a white solid. HPLC, Rt: 6.14 min (purity=99.5%). LC/MS: M+(ESI): 514.3.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(P(N(C)C)(N(C)C)=O)C.C([Li])CCC.[CH3:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([O:38][CH2:39][CH2:40]Cl)=[CH:30][CH:29]=1>C1COCC1.O>[C:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:40][CH2:39][O:38][C:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]([CH3:27])=[CH:29][CH:30]=1)([OH:10])=[O:9]
Reactant: O=C(O)Cc1ccccc1
Reactant: Cc1ccc(OCCCl)c2ccccc12
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(OCCC(C(=O)O)c2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a 1 1. three-neck round bottom flask fitted with a thermometer, nitrogen inlet tube, addition funnel and magnetic stirrer was added 5.9 g (43.6 mmol) of phenylacetic acid and 250 ml of tetrahydrofuran. To the mixture was added 7.6 ml (43.6 mmol) of HMPA. The mixture was cooled to approximately 0° C. and 6.4 ml (89.4 mmol) of 1.48M n-butyllithium was added dropwise to the reaction mixture. The mixture was warmed to room temperature over a period of approximately 50 minutes and cooled to approximately -78° C. To the reaction mixture was added a solution of 2-(4-methyl-1-naphthalenyloxy)ethyl chloride dissolved in 100 ml of THF. The reaction mixture was stirred at room temperature overnight and diluted with water. The mixture was washed twice with diethyl ether and the resulting aqueous phase was acidified. The aqueous phase was extracted twice with diethyl ether and the organic extracts were combined, washed twice with water, once with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The volatile constituents were evaporated under vacuum to provide 9.53 g of a light tan solid. The solid was recrystallized from diethyl ether and hexane to provide 5.62 g of the desired product. mp=130°-131.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:11]([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[O:12])=CN(C)C)=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1.O1CCOCC1>O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:11]([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[O:12])=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1
Reactant: Cc1ccsc1C(=O)C(=CN(C)C)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccsc1C(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 59.9 %

Procedure:
A stirred solution of 6.0 g of 4-chloro-β-(dimethylamino)-α-(3-methyl-2-thienoyl)-2-nitrosty rene, 50 ml of 1,4-dioxane and 10 ml of water was refluxed for 16 hr and allowed to cool. The cooled solution was concentrated, and the residue was partitioned between dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. A stirred solution of the residue, dioxane and water was refluxed overnight and was worked-up as above. The residue was purified by preparative HPLC (Waters Associates Prep LC./Model 500, silica gel, sample applied in dichloromethane (20 ml), eluted with dichloromethane, 200 ml/min flow rate, Gow Mac Model 80-800 UV detector). The appropriate fractions were concentrated and the residue was recrystallized from 95% ethanol to give 3.03 g of product, mp 105°-107° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[CH2:17]1[O:19][CH2:18]1.[ClH:20]>C(O)C.CCOCC>[ClH:20].[OH:19][CH2:18][CH2:17][N:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[CH2:12]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCCC2
Reactant: C1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc2c(c1)CN(CCO)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 8-nitro-2,3,4,5-tetrahydro-1H-2-benzazapine (5.08 g, 22.2 mmol) in ethanol (200 ml) at 0° C. was added 2.5M sodium hydroxide solution (10.0 ml). To this solution, in a pressure bottle, was added ethylene oxide (4.2 ml) and the bottle was capped and stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the residue was partitioned between dichloromethane and dilute sodium hydroxide. The organic phase was dried (magnesium sulfate) and concentrated to give a yellow solid. This solid was taken up in ethanol and acidified with hydrochloric acid in ethanol. Addition of ether effected precipitation of the title salt as an orange solid (2.69 g, 44%). m.p. 193.5-4.5° C.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[CH:11]=1)(=O)OCC)C.C(O[K])(C)(C)C.O=[C:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.P(=O)([O-])[O-]>O1CCCC1>[C:43]([O:42][C:40]([N:37]1[CH2:38][CH2:39][C:34](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=3)[CH:11]=2)[CH2:35][CH2:36]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CCOP(=O)(Cc1cccc(Oc2ccc(C(F)(F)F)cn2)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)O[K]
Agent: O=[PH]([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 48.9 %

Procedure:
To a stirred mixture of [3-(5-trifluoromethyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester (155.7 g, 0.40 mol) in tetrahydrofuran (800 mL) at −10° C. was added dropwise over a 5 min period 1.0 M tBuOK in tetrahydrofuran (420.0 mL, 0.42 mol). The temperature rose to −3° C. during the addition. The resulting red mixture was stirred between −6° C. and −10° C. for 2.5 h. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (79.7 g, 0.40 mol) in tetrahydrofuran (300 mL) was added dropwise over a 5 min period. The temperature rose to 2° C. The resulting red mixture was stirred at temperatures reaching 21° C. over the next 16 h. TLC showed product with no phosphonate present. The mixture was poured into 3.5 L of stirred ice-water. The resulting suspension was stirred at ambient temperature for 2.5 h and then was extracted with successive 1.0 L and 0.6 L portions of dichloromethane. The combined extracts were washed with 500 mL of brine, dried over magnesium sulfate and concentrated in vacuo to a thick semi solid residue. 250 mL of methyl t-butyl ether was added. The suspension was stirred at −10° C. for 2 h and filtered. Drying in vacuo at 25° C. for 66 h provided 85 g (49%) of product. The filtrate was concentrated in vacuo to a damp solid residue. This was taken up in 100 mL of methyl t-butyl ether. To the stirred suspension was added 300 mL of heptane and the resulting suspension was stirred at −10° C. for 2 h. The solid was filtered off, rinsed with 50 mL of methyl t-butyl ether:heptane (1:3) and pressed dry under suction. Further drying in vacuo at 34° C. for 6 h provided an additional 34.2 g (19.5%) of product. Total yield=119.2 g (68.5%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[CH2:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C@H:55]([NH2:62])[C@@H:54]1[OH:63].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[OH:63][C@@H:54]1[CH2:53][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C@@H:55]1[NH:62][C:43]([C:42]1[CH:47]=[CH:48][CH:49]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:44]
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@H]1c2ccccc2C[C@H]1O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl) (1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.619 mmol) in a tetrahydrofuran/water mixture (2.50 mL/1.00 mL) was added lithium hydroxide monohydrate (0.0780 g, 1.86 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), (1S,2R)-(−)-cis-1-amino-2-indanol (0.277 g, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This mixture was stirred for 18 h at ambient temperature. After the mixture was extracted with ethyl acetate (2×), the combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 40–100% ethyl acetate/hexanes gave the title compound (0.342 g, 72% yield). ES-MS (m/z) 521 [M+1(−Tr)]+
Reaction SMILES: [O:1]([CH:8]1[CH2:12][NH:11][CH2:10][CH:9]1[OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)[CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19](=[O:20])[CH2:18][CH2:17][N:11]2[CH2:12][C@@H:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@H:9]([OH:13])[CH2:10]2)=[CH:26][CH:25]=1
Reactant: CN(C)CCC(=O)c1ccc(F)cc1
Reactant: OC1CNCC1Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCN1C[C@@H](O)[C@H](Oc2ccccc2)C1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A mixture of 3.6 g. (0.02 mole) of 4-phenoxy-3-pyrrolidinol, 5 g. (0.0215 mole) of β-dimethylamino-p-fluoropropiophenone hydrochloride, 10 g. of potassium carbonate and 50 ml. of dimethylformamide was heated with stirring at 70° C. for 6 hr. while nitrogen gas was bubbled through the reaction mixture. The mixture was poured into water and extracted twice with benzene. The combined extracts were dried over anhydrous sodium sulfate and concentrated to give 6.1 g. of an oil as residue. The oil was chromatographed on 130 g. of silica gel. The desired compound was eluted with 20% acetone in benzene and 2.6 g. (39%) of an oil which gradually crystallized upon standing was obtained. This solid was recrystallized from petroleum ether diethylether to yield a white solid, m.p. 77°-80° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[O:7][C:8]1[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=[C:10]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[NH:28])[NH2:27])[CH:21]=2)[N:9]=1)(=[NH:3])[NH2:2].[ClH:32]>>[ClH:32].[ClH:32].[C:1]([C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[O:7][C:8]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=[C:10]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[NH:27])[NH2:28])[CH:21]=2)[N:9]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)c1ccc(Oc2cccc(C(=N)N)c2)nc1Oc1cccc(C(=N)N)c1
Agent: Cl
Product: N=C(N)c1cccc(Oc2ccc(C(=O)O)c(Oc3cccc(C(=N)N)c3)n2)c1
Temperature: 80 °C

Procedure:
In a manner similar to Example 2 above, 2,6-bis(3-amidinophenoxy)-pyridine-3-carboxylic acid, ethyl ester (0.20 g, 0.31 mmol) was dissolved in 5M HCl and heated for 2 hours at 80° C. The solvent was removed in vacuo to give 2,6-bis(3-amidinophenoxy)pyridine-3-carboxylic acid, dihydrochloride; NMR (DMSO-d6) 9.5 (br s,4), 9.35 (br s,4), 8.45 (d,1), 7.7 (m,2), 7.6 (m,2), 7.5 (m,4), 6.95 (d,1) ppm.