Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([NH:7][CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)C=CC=CC=1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[S:25]([NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31](Cl)=[O:32])(=[O:27])=[O:26])[CH:18]=[CH:17][CH:16]=1>>[C:19]1([CH:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:7][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[NH:28][S:25]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:24]=2[N:15]=[CH:16][CH:17]=[CH:18]3)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1NS(=O)(=O)c1cccc2cccnc12
Reactant: c1ccc(NCc2cccnc2)cc1
Product: O=C(NC(c1ccccc1)c1cccnc1)c1ccccc1NS(=O)(=O)c1cccc2cccnc12
Yield: 40.5 %

Procedure:
120 mg of phenylpyridin-3-ylmethylamine (Synthesis 1976, 593) were reacted with 450 mg of 2-(quinoline-8-sulfonylamino)-benzoyl chloride in analogy to example 1 which resulted in 130 mg of an amorphous solid. Rf(EA)=0.29. MS (ES): 495 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([N:18]=COC)=[CH:16][C:15]([C:22]2[N:26]=[CH:25][O:24][N:23]=2)=[N:14]1.S(=O)(=O)(O)O>CC(C)=O.O>[NH2:18][C:17]1[N:13]([C:3]2[C:4]([Cl:12])=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]=2[Cl:1])[N:14]=[C:15]([C:22]2[N:26]=[CH:25][O:24][N:23]=2)[CH:16]=1
Reactant: COC=Nc1cc(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: Nc1cc(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 78.4 %

Procedure:
1-(2,6-Dichloro-4-trifluoromethylphenyl)-5-methoxymethylideneamino-3-(1,2,4-oxadiazol-3-yl)pyrazole (2.80 g, 6.89 mmol) was dissolved in a mixed solvent of 50 ml of acetone and 5 ml of water, and then concentrated sulfuric acid (0.70 g, 6.92 mmol) was added with stirring at room temperature. The mixture was stirred at room temperature for 48 hours and the reaction solution was concentrated under reduced pressure. The pH of the residue was adjusted to about 8 by adding an aqueous saturated sodium hydrogencarbonate solution, followed by extracting three times with 30 ml of ethyl acetate. The organic layer was washed three times with 100 ml of water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting concentrated residue was subjected to silica gel column chromatography [eluent: mixed solvent of ethyl acetate and hexane (volume ratio=1:2)] to obtain 1.96 g (5.40 mmol) of the title compound as a colorless crystal.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:13]=[C:12]([Cl:14])[C:11]([F:15])=[CH:10][C:8]=1[NH2:9].[F:16][B-:17]([F:20])([F:19])[F:18].[H+].[N:22]([O-])=O.[Na+]>O>[F:16][B-:17]([F:20])([F:19])[F:18].[Cl:6][C:7]1[CH:13]=[C:12]([Cl:14])[C:11]([F:15])=[CH:10][C:8]=1[N+:9]#[N:22]
Reactant: O=N[O-]
Reactant: Nc1cc(F)c(Cl)cc1Cl
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#[N+]c1cc(F)c(Cl)cc1Cl

Procedure:
165 ml of tetrahydrofuran are added to 100 g of 2,4-dichloro-5-fluoroaniline at room temperature. To this solution are added 333 ml of tetrafluoroboric acid (50% strength) with cooling. 57.5 g of sodium nitrite in 117 ml of water are added to the reaction mixture cooled to 5°-10° C. in such a way that the internal temperature is 7°-13° C. After addition is completed, the 0° C. solution is filtered. The residue is washed with tetrahydrofuran and ice-cold water. 121 g of product remain.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH3:9].C([Li])CCC.CN([CH:18]=[O:19])C>CCOCC.CCCCCC>[CH3:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: Cc1cncc(C)c1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cncc(C)c1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-3,5-dimethylpyridine (0.70 g, 3.76 mmol) in ether (10 mL) was cooled to −78° C. and then 2.50 M n-butyllithium in hexane (1.50 mL) was added to the reaction flask dropwise. After stirring at −78° C. for 1 h, DMF (1.75 mL, 22.6 mmol) was added to the reaction flask slowly. The reaction solution was allowed to warm to room temperature overnight. The reaction was quenched with 10 mL saturated NH4Cl solution and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate once. The combined organic solutions were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (40% to 50% ethyl acetate/hexanes) to afford the desired product as a solid. (280 mg, 55%). 1H NMR (400 MHz, CDCl3): δ 10.62 (s, 1 H), 8.43 (s, 2 H), 2.57 (s, 6 H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:16][CH2:15][CH:12]1[CH2:13][CH2:14][N:9]([C:7]2[O:6][N:5]=[C:4]([CH:2]([CH3:1])[CH3:3])[N:8]=2)[CH2:10][CH2:11]1)(=[O:27])=[O:26]
Reactant: CC(C)c1noc(N2CCC(CO)CC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Step 3, 174 g, 0.77 mol) and triethylamine (140 mL, 1.0 mol) in dichloromethane (1 L) at 5° C. was treated with a solution of methanesulfonyl chloride (69 mL, 0.89 mol) in dichloromethane (150 mL) over a 1 h period. The mixture was stirred at 5° C. for 30 min, and then was quenched by the addition of water (400 mL). The mixture was stirred for 30 min, and then the organic extract was washed with water (2×400 mL), dried (MgSO4) and concentrated. The residue was treated with heptane (1 L), stirred for 3 h, and the resulting solid was collected by filtration (heptane wash) and air-dried to afford {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (219.7 g, 94%) as an off-white solid. 1NMR (400 MHz, CDCl3): δ 4.21-4.15 (m, 2H), 4.08 (d, 2H, J=6.6 Hz), 3.04 (m, 2H), 3.01 (s, 3H), 2.86 (septet, 1H, J=6.9 Hz), 2.05-1.93 (m, 1H), 1.88-1.81 (m, 2H), 1.43-1.31 (m, 2H), 1.26 (d, 6H, J=6.8 Hz); LRMS (ESI), m/z 304 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.COC(C)(C)C.CC(C)([O-])C.[Na+].[N:32]1([C:38](=[O:40])[CH3:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.O1CCOCC1>[C:38]([N:32]1[CH2:37][CH2:36][N:35]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH2:34][CH2:33]1)(=[O:40])[CH3:39]
Reactant: CC(=O)N1CCNCC1
Reactant: O=S(=O)(Cc1ccccc1)NCc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(CNS(=O)(=O)Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.8 %

Procedure:
In a flask, N-[(4-bromophenyl)methyl]-1-phenyl-methanesulfonamide (2.79 g, 8.20 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2 aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (60 mg, 0.082 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (39 mg, 0.0820 mmol) and sodium tert-butoxide (1.22 g, 12.3 mmol) were combined and purged with nitrogen. 1,4-Dioxane (40 mL) and 1-piperazin-1-ylethanone (1.58 g, 12.3 mmol) were then added and the reaction was stirred at ambient temperature for 16 hours. The precipitate was collected by filtration, washed with DCM and then with water and dried under vacuum overnight to give N-[[4-(4-acetylpiperazin-1-yl)phenyl]methyl]-1-phenyl-methanesulfonamide (1.52 g, 48% yield). LCMS (m/z) ES+ 388.2 [M+1]+.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=O)[C:21]([O:23][CH3:24])=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCCCCC.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[C:20](=[CH:1]\[CH3:2])/[C:21]([O:23][CH3:24])=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: COC(=O)C(=O)c1ccccc1OCc1ccccc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C/C=C(/C(=O)OC)c1ccccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 57 %

Procedure:
At 0° C. and under nitrogen, 32 ml (50 mmol) of a 1.6 molar solution of n-butyllithium in hexane is slowly added to 18.5 g (50 mmol) of ethyltriphenylphosphonium bromide in 100 ml of absolute tetrahydrofuran. After the mixture has been stirred for 30 minutes, 13.5 g (50 mmol) of methyl 2-(benzyloxy)-phenylglyoxylate in 25 ml of absolute tetrahydrofuran is dripped in at 0° C. The mixture is stirred for 16 hours at room temperature. After concentration, the residue is taken up in dichloromethane and washed several times with water. After drying over Na2SO4 the solvent is evaporated off. The crude product obtained is purified by chromatography (a 9:1 mixture of cyclohexane and ethyl acetate). There is obtained 8.0 g (57%) of the methyl crotonate (trans:cis ratio=9:1) as an oil.
Reaction SMILES: [I-].[CH2:2]([N+:4]1([CH2:15][CH3:16])[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6][CH:5]1[CH3:14])[CH3:3].[OH2:17]>>[OH-:17].[CH2:15]([N+:4]1([CH2:2][CH3:3])[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6][CH:5]1[CH3:14])[CH3:16].[CH2:15]([N+:4]1([CH2:2][CH3:3])[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6][CH:5]1[CH3:14])[CH3:16]
Reactant: O
Agent: CC[N+]1(CC)C(C)CCC2CCCCC21
Agent: [I-]
Product: [OH-]
Temperature: 25 °C

Procedure:
The hydroxide version of N,N-diethyl-2-methyldecahydroquinolinium cation was prepared by ion exchange as described in the procedure below. To a solution of 20 gm (0.06 mol) of N,N-diethyl-2-methyldecahydroquinolinium iodide in 80 ml water, 80 gm of OH-ion exchange resin (BIO RAD® AGI-X8) was added, and the resulting mixture was allowed to gently stir at room temperature for few hours. The mixture was filtered and the ion exchange resin was rinsed with additional 30 ml water (to ensure removing all the cations from the resin). The rinse and the original filtrate were combined and titration analysis on a small sample of the filtrate with 0.1 N HCl indicated a 0.5M OH ions concentration (0.055 mol cations). Scheme 1 below depicts the synthesis of the templating agent.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][NH:4][N:3]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.IC1C=NC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]>[Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Brc1cccnc1
Reactant: CC(=O)Nc1c[nH]nc1Cl
Agent: [Cu]
Agent: CNCCNC
Agent: Ic1cccnc1
Product: CC(=O)Nc1cn(-c2cccnc2)nc1Cl

Procedure:
In step c of Scheme 1, N-(3-chloro-1H-pyrazol-4-yl)acetamide (1b) is reacted with a halopyridine such as 3-bromopyridine or 3-iodopyridine in the presence of a copper salt (such as copper(I) chloride (CuCl), copper(II) chloride (CuCl2), or copper(I) iodide (CuI)), potassium phosphate (K3PO4), and N,N′-dimethylethane-1,2-diamine to yield N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1c). It has been discovered that when copper(I) iodide is used that the yield of the reaction is greatly affected by the quality of the copper(I) iodide. The process may be conducted in a polar solvent, such as, acetonitrile (MeCN), dioxane, or N,N-dimethylformamide at a temperature between about 50° C. and about 110° C. It was surprisingly discovered that the addition of water during the work-up of this step maximizes the yield. Further, this synthetic method is simpler and reduces the costs of starting materials over known heteroarylation methods.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[H-].[Na+].O>CN(C=O)C>[CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH:3]1[O:5][CH2:4]1
Reactant: BrCC1CO1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)ccn2CC1CO1
Temperature: 60 °C

Procedure:
Epibromohydrin (0.73 ml, 8.5 mmole) was added to a stirred solution of indole (1.0 g, 8.5 mmole) and sodium hydride (0.34 g, 8.5 mmole) in anhydrous DMF (20 ml), and the mixture was heated at 60° C. under nitrogen for two hours. Water (100 ml) was added and the product extracted into CH2Cl2 (3×25 ml). The combined organics were washed with water (25 ml), brine (25 ml) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a light yellow colored oil (1.45 g). This was purified by flash silica gel chromatography (30% ethyl acetate in hexane) to afford the titled product as a light oil (1.37 g, 93% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C@H:16]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[N:23]([CH2:27][CH2:28][O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[N:22]=[CH:21]5)[CH3:17])=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.[H-].[Na+].BrCCOC1CCCCO1>C1COCC1.C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C@H:16]([C:18]4[CH:19]=[CH:20][C:21]5[C:25](=[CH:24][N:23]([CH2:27][CH2:28][O:29][CH:30]6[CH2:35][CH2:34][CH2:33][CH2:32][O:31]6)[N:22]=5)[CH:26]=4)[CH3:17])=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: C[C@@H](c1ccc2c(cnn2CCOC2CCCCO2)c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Agent: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H](c1ccc2nn(CCOC3CCCCO3)cc2c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-(1-Methyl-1H-pyrazol-4-yl)-3-((S)-1-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indazol-5-yl}-ethyl)-imidazo[1,2-b]pyridazine (Example 195, 34 mg, 0.1 mmol) was added to a suspension of NaH (55%, 4.8 mg 0.11 mmol) in dry THF (0.5 mL) at 0° C. The RM was allowed to stir at rt for 15 min and 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.024 mL, 0.150 mmol) was added at 0° C. It was stirred additionally 7 h at rt, then overnight at 60° C., and finally 7 h at 120° C. in a pressure safe capped vial. After cooling at rt the RM was taken-up in DCM, washed with brine, the organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, EtOAc/MeOH=100:0->80:20) to afford 6-(1-methyl-1H-pyrazol-4-yl)-3-((S)-1-{2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-2H-indazol-5-yl}-ethyl)imidazo[1,2-b]pyridazine and the title compound (tR 4.05 min (conditions 2), MH+=472.3).
Reaction SMILES: C(OC(=O)C)C.[ClH:7].P(O[CH2:21][N:22]1[C:31]2[C:26](=[C:27]([F:36])[CH:28]=[CH:29][C:30]=2[O:32][CH2:33][CH2:34][CH3:35])[C:25](=[O:37])[C:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:23]1)(OC(C)(C)C)(OC(C)(C)C)=O>C(OCC)(=O)C>[Cl:7][CH2:21][N:22]1[C:31]2[C:26](=[C:27]([F:36])[CH:28]=[CH:29][C:30]=2[O:32][CH2:33][CH2:34][CH3:35])[C:25](=[O:37])[C:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:23]1
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(COP(=O)(OC(C)(C)C)OC(C)(C)C)c12
Reactant: Cl
Solvent: CCOC(C)=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCl)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A 4N hydrogen chloride ethylacetate solution (2 ml) was added to an ethyl acetate solution (3 ml) of di-tert-butyl 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl phosphate (300 mg, 0.55 mmol) while ice-cooling and the mixture was stirred at room temperature for 2 hours. The deposited insoluble matter was collected by filtration and dried, giving a white powder of 1-chloromethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (18 mg, yield: 92%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:2][C:3]([NH:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([NH:14][CH2:15][CH2:16][O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:29][CH2:28]1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Reactant: CN1CCNCC1
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)COC(NCCOc2ccccc2)=N3)CC1
Yield: 101.1 %

Procedure:
Prepared from the above described 2-chloro-N-[2-(2-phenoxy-ethylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (180 mg, 0.50 mmol; HPLC 1.096 min) and 1-methylpiperazine (1.1 ml, 10 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (214 mg, 100%; HPLC 0.494 min), MS (ISP) m/e=424.1 [(M+H)+].
Reaction SMILES: [C:1]([C@@]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)C1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.[C@@H:38]1([N:46]2[C:56]3[N:55]=[C:53]([NH2:54])[NH:52][C:50](=[O:51])[C:49]=3[N:48]=[CH:47]2)[O:45][C@H:42]([CH2:43][OH:44])[C@@H:40]([OH:41])[CH2:39]1>>[C:1]([O:41][C@@H:40]1[C@@H:42]([CH2:43][OH:44])[O:45][C@@H:38]([N:46]2[C:56]3[N:55]=[C:53]([NH2:54])[NH:52][C:50](=[O:51])[C:49]=3[N:48]=[CH:47]2)[CH2:39]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)O[C@H]1C[C@H](n2cnc3c(=O)[nH]c(N)nc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
This compound was prepared using the procedure for Palmitoyl-2'-deoxyguanosine, substituting the appropriate amount of 5'-O-dimethoxytrityl-deoxyguanosine for 2'-deoxyguanosine monohydrate and deprotecting the 5'hydroxyl group as follows: removing the dimethoxytrityl group by stirring in 80% aqueous acetic acid at 25 degrees C. for 1 hour, isolating the crude product by filtration, triturating the crude product for 1 hour in methanol, recovering the product by filtration and drying.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[CH3:1][O:2][CH2:3][C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH:18][C:29](=[O:30])[CH2:28][C:23]2[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:5])[CH3:6]
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)COC)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)COC)cn1

Procedure:
2-Amino-pentanoic acid [1-(2-methoxy-1,1-dimethyl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: H1NMR (400 MHz, CDCl3) 0.85 (t, 3H, J=7), 1.3 (m, 2H), 1.54 (s, 6H), 1.65 (m, 1H), 1.80 (m, 1H), 3.29 (s, 3H), 3.43 (s, 2H), 3.53 (s, 3H), 4.76, (m, 1H), 6.56 (m, 1H), 6.71 (m, 1H), 6.81 (m, 2H), 7.44 (s, 1H), 7.65 (s, 1H); MS m/z 423.3 (M+1).
Reaction SMILES: O[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Al+3].[Cl-].[Cl-].[Cl-].[OH-].[Na+].[C:20]1([O:26][CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:27][O:26][C:20]1[CH:25]=[CH:24][C:23]([C:2]2([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]2)=[CH:22][CH:21]=1
Reactant: COc1ccccc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: COc1ccc(C2(c3ccccc3)CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Hydroxy-4-phenylpiperidine (5.00 g, 28.2 mmol, 1.00 equiv, Aldrich) was added to a suspension of AlCl3 (18.8 g, 141 mmol, 5.00 equiv) in anhydrous anisole (100 mL). The mixture was stirred at room temperature for 1 hour and then heated to 50° C. for 3.5 hours. It was cooled to room temperature and poured cautiously into ice-water. The mixture was basified to pH 11 by addition of 6 M aqueous NaOH, and extracted with EtOAc (3×75 mL). The combined organic solutions were applied directly to a flash chromatography column, which was eluted with CH2Cl2—NH3 in MeOH (0.67 M), 4:1 to afford 1.683 g (22%) of light yellow oil, which was characterized spectroscopically.
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]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([N:50]3[CH2:55][CH2:54][CH2:53][N:52]([CH2:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:51]3=[O:63])[CH:48]=[CH:49][C:6]=2[N:5]=1)[CH2:2][CH3:3].CO>Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[CH:46]=[C:47]([N:50]3[CH2:55][CH2:54][CH2:53][N:52]([CH2:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C:51]3=[O:63])[CH:48]=[CH:49][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(N3CCCN(Cc4ccccc4)C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: CCCc1nc2ccc(N3CCCN(Cc4ccccc4)C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 55 from 4'-[[2-n-propyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanol in methanolic hydrochloric acid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][CH2:19][C:20]2=[O:25])[CH:14]=[CH2:15].[CH3:26][Si:27](Cl)([CH3:29])[CH3:28]>O1CCCC1.CCOCC.O>[CH3:26][Si:27]([CH3:29])([CH3:28])[O:25][C:20]1[C:21]2[C:17](=[C:16]([CH2:13][CH:14]=[CH2:15])[CH:24]=[CH:23][CH:22]=2)[CH2:18][CH:19]=1
Reactant: C=CCc1cccc2c1CCC2=O
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CCOCC
Product: C=CCc1cccc2c1CC=C2O[Si](C)(C)C
Reaction time: 1 h

Procedure:
1.24 ml of diisopropylamine and 6 ml of tetrahydrofuran are cooled to -40° C., then 4.7 ml of butyllithium is added drop by drop. The temperature is allowed to rise to -20° C., agitation is carried out for 1/4 hour, then 1 g of 4-(2-propenyl)-1-indanone in 10 ml of tetrahydrofuran is introduced at -70° C. After agitation for one hour at -60° C., 1.15 ml of trimethylsilyl chloride in 6 ml of tetrahydrofuran is added, with agitation for one hour at -60° C. The mixture is poured over 100 ml of water and ice and 100 ml of ether. After decanting, the aqueous phase is extracted with ether, the organic phases are reunited, dried and concentrated to dryness without heating, and 1.51 g of expected product is isolated.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[ClH:20].[CH3:21][NH:22][CH3:23]>>[ClH:20].[ClH:20].[CH3:21][N:22]([CH2:16][C:15]1[CH:18]=[CH:19][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[O:11])=[CH:13][CH:14]=1)[CH3:23]
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: CNC
Agent: Cl
Product: CC(C)N1CCN(C(=O)c2ccc(CN(C)C)cc2)CC1

Procedure:
Prepared from the product of Example 15 and dimethylamine hydrochloride.