Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:20](O)[C:21]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=1[F:29])[CH2:10][C:11]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C>CO>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=1[F:29])[CH2:10][C:11]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OC1CCCCC1)C(O)c1cc(F)c(F)cc1F
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OC1CCCCC1)Cc1cc(F)c(F)cc1F
Yield: 79 %

Procedure:
In accordance with the method described in Example 6, except that 43.14 g (3S)-cyclohexyl 3-(tert-butoxycarbonylamino)-4-hydroxy-4-(2,4,5-trifluorophenyl)butyrate and an equal amount of anhydrous ethanol were used to replace (3S)-3-(tert-butoxycarbonylamino)-4-hydroxy-4-(2,4,5-trifluorophenyl)n-butyl ester and methanol respectively, 32.82 g (R)-cyclohexyl 3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butyrate (yield: 79%) was obtained using the same method.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH2:8][CH2:7][CH2:6][N:5]3[C:4]1=[O:15].[CH3:16]I.O>CN(C)C=O>[CH3:16][N:3]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH2:8][CH2:7][CH2:6][N:5]3[C:4]1=[O:15]
Reactant: O=c1[nH]c2cccc3c2n1CCC3
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n2c3c(cccc31)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (2.36 g) was added to a solution of 5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (10 g) obtained in Reference Example 131 in dimethylformamide (100 ml), the mixture was stirred at room temperature for 1 hour, methyl iodide (3.68 ml) was added, and the mixture was stirred at room temperature for 18 hours. Water (200 g) was poured into the reaction mixture, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a pale yellow solid (9.7 g). Further recrystallization from water-ethyl acetate afforded the title compound as colorless crystals (9.0 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[N:12]([CH2:15][C:16]3[N:17]=[CH:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12>C(O)(=O)C.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[N:12]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)N(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CN1CCc2c(C)c3ccccc3n2C1=O
Temperature: 65 °C
Yield: 90.6 %

Procedure:
A solution of 3,4-dihydro-5-methyl-2-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrimido[1,6-a]indol-1(2H)-one (0.9 g) in a mixture of acetic acid and water (4:1, 30 ml) was heated at 65° C. for 3.5 hours. After evaporation of the solvent, the residue was neutralized with aqueous sodium bicarbonate solution and extracted three times with chloroform. The chloroform layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (5% methanol-chloroform) to give 3,4-dihydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)-methyl]pyrimido[1,6-a]indol-1(2H)-one (0.447 g) as a powder. This powder was dissolved in a mixture of methanol (40 ml) and 12N hydrochloric acid (0.3 ml). The solution was evaporated to 4 ml and then diluted with ether. The solution was allowed to stand at room temperature to give 3,4-dihydro-5-methyl-2-[(5-methyl- 1H-imidazol-4-yl)methyl]pyrimido[1,6-a]indol-1(2H)-one hydrochloride (387 mg).
Reaction SMILES: [C:1]1([CH:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)(Cl)Cl>[C:28]([N:12]1[CH2:11][CH2:10][C:9]2([C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8]2)[CH2:14][CH2:13]1)(=[O:30])[CH3:29]
Reactant: c1ccc(C2OC3(CCNCC3)c3ccccc32)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold stirred solution of 6.0 g. of 1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] (Example 65), 2.4 g. of triethylamine, and 50 ml. of chloroform is added dropwise a solution of 2.0 g. of acetyl chloride and 50 ml. of chloroform. The mixture is stirred for 2 hours at room temperature, washed with water, dried over sodium sulfate, and concentrated. The residue is recrystallized from chloroform to provide colorless crystals, m.p. 128°-130°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[F:22][C:23]([F:34])([F:33])[CH2:24]OS(C(F)(F)F)(=O)=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:24][C:23]([F:34])([F:33])[F:22])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)[nH]n1
Product: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F

Procedure:
In analogy to the procedure described for example 13 a], 5-(4-trifluoromethoxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (example 11 b]) was reacted with trifluoroethyltriflate to give 2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazole-3-carboxylic acid ethyl ester as colorless solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[F:21][C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1C(Cl)=O>C(#N)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[C:23]1[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:22]=1[F:21])[CH3:9]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Yield: 94 %

Procedure:
To an oven-dried flask was added potassium ethyl malonate (3.66 g, 21.5 mmol) and freshly distilled acetonitrile (70 mL). The mixture was cooled to 10° C. to 15° C. and stirred under an atmosphere of nitrogen and to it added anhydrous magnesium chloride (2.44 g, 25.7 mmol) and triethylamine (2.05 g, 20.3 mmol). The mixture was then stirred at room temperature under nitrogen for 2.5 hours. The resultant white slurry was recooled to 0° C. and 2,4,5-trifluorobenzoyl chloride was added over a period of 15 minutes, followed by more triethylamine (0.23 g, 2.3 mmol). The mixture was then stirred at room temperature overnight under nitrogen. Acetonitrile was then removed in vacuo and toluene (30 mL) was added. The mixture was reconcentrated and more toluene (60 mL) then added. Hydrochloric acid (1.5 M, 40 mL) was cautiously added, ensuring that the temperature did not exceed 25° C., and the aqueous layer separated. The organic fraction was washed with 1.5 M HCl (2×25 mL) and water (2×25 mL), dried over MgSO4, and solvent removed in vacuo to afford 3-oxo-3-(2,4,5-trifluoro-phenyl)-propionic acid ethyl ester as a pale orange solid (2.35 g, 9.55 mmol, 94%).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[N:20]=[C:21]([CH3:24])[S:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:11][C:9]1[S:10][C:6]2[C:5]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=[C:2]([NH:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[C:7]=2[N:8]=1
Reactant: Cc1nc(N)cs1
Reactant: Cc1nc2c(Cl)ncc(-c3cccnc3)c2s1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1nc(Nc2ncc(-c3cccnc3)c3sc(C)nc23)cs1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
4-Chloro-2-methyl-7-pyridin-3-yl-thiazolo[4,5-c]pyridine (100 mg, 0.38 mmol) and 4-amino-2-methylthiazole (44 mg, 0.38 mmol) (Example C) were dissolved in 3 ml dry dioxane. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (44 mg, 0.08 mmol) and cesium carbonate (200 mg, 0.61 mmol) were added and this mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Tris(dibenzylideneacetone)dipalladium chloroform complex (38 mg, 0.035 mmol) was added and the reaction mixture was stirred for 1 hour at 100° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10->0:100 gradient) and recrystallization in diisopropylether. The desired product was obtained as a yellow solid (20 mg, 15%), MS: m/e 354.1 (M+H+).
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[Si:14]([O:21][CH2:22][CH2:23][CH2:24][C@H:25]([O:30][C:31]1[N:36]=[CH:35][N:34]=[C:33]2[N:37]([C:40]3[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][N:41]=3)[N:38]=[CH:39][C:32]=12)[C:26](OC)=[O:27])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[Si:14]([O:21][CH2:22][CH2:23][CH2:24][C@H:25]([O:30][C:31]1[N:36]=[CH:35][N:34]=[C:33]2[N:37]([C:40]3[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][N:41]=3)[N:38]=[CH:39][C:32]=12)[C:26]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)=[O:27])([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:15])[CH3:16]
Reactant: COC(=O)[C@H](CCCO[Si](C)(C)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Reactant: N#Cc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C#N)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
A solution of trimethylaluminium (2M in toluene) (0.795 mL, 1.59 mmol) was added dropwise to a stirred solution of 6-aminonicotinonitrile (165 mg, 1.38 mmol) in toluene (5 mL) cooled to 0° C., over a period of 1 minute under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. A solution of (2S)-methyl 5-(tert-butyldimethylsilyloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)pentanoate (Intermediate O2) (680 mg, 1.38 mmol) in toluene (5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 10 minutes allowed to warm to ambient temperature and then heated at reflux for 18 hours. The reaction mixture was allowed to cool to r.t. and concentrated. The residue was diluted with ethyl acetate and treated with 1M citric acid (2 ml). The layers were separated and the organics were washed with water and brine, dried (MgSO4) and evaporated to afford the product (797 mg) which was used without further purification. m/z (ES−) (M−H)−=577.45; HPLC tR=3.29 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:13]3[NH:14][C:15]([C:17]([O:19]C)=[O:18])=[CH:16][C:12]=3[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Li+].CO>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:13]3[NH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:12]=3[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cc2c([nH]1)C(c1cccc(C#N)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cccc(C2CCc3cc(C(=O)O)[nH]c32)c1
Yield: 34 %

Procedure:
The title compound was synthesized from methyl 6-(3-cyanophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.027 g, 0.10 mmol) and lithium hydroxide (0.044 g, 1.0 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (5-6 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-80% MeOH: water (with 0.1% formic acid) to afford a light pink solid: 8.6 mg (34% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.21-2.30 (m, 1H) 2.65 (s, 1H) 2.76 (s, 1H) 2.93-3.03 (m, 1H) 4.33 (s, 1H) 6.68 (s, 1H) 7.40-7.44 (m, 1H) 7.44-7.49 (m, 2H) 7.54-7.58 (m, 1H); LC-MS ESI− 251.2 (m−H); HPLC (UV=97.75%), (ELSD=100%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.[N:14]([C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)=[C:15]=[O:16].C(N(CC)CC)C>C1COCC1>[NH:21]1[C:22]2[C:18](=[C:17]([NH:14][C:15](=[O:16])[O:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=3)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: O=C=Nc1cccc2[nH]ccc12
Reactant: OCc1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2[nH]ccc12)OCc1ccc(OC(F)(F)F)cc1
Yield: 54.4 %

Procedure:
[4-(Trifluoromethoxy)phenyl]methanol (0.13 g, 0.7 mmol) and the product of Example 80A (0.1 g, 0.63 mmol) in THF (5 mL) were heated at reflux for 16 hours with a catalytic amount of triethylamine. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether/hexane to provide the title compound as tan crystals (0.12 g). 1H NMR (300 MHz, DMSO-d6) δ 5.21 (s, 2H), 6.73 (s, 1H), 7.0 (t, 1H), 7.1 (d, 1H), 7.23 (t, 1H), 7.38 (dd, 1H), 7.4 (d, 2H), 7.6 (d, 2H), 9.5 (s, 1H), 11.06 (s, 1H).). Anal. Calcd. for C17H13N2F3O3.0.25 H2O: C, 57.55; H, 3.84; N, 7.90. Found: C, 57.42; H, 3.81; N, 7.32
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[C:21](=[O:22])[C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:12][O:13][C:9]=2[CH2:8][CH2:7]1)[CH3:4].Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37]CNC[CH2:33]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>O>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[C:10]2[C:21](=[O:22])[CH:6]([CH2:5][N:3]3[CH2:2][CH2:33][N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[O:25][CH3:24])[CH2:37][CH2:4]3)[CH2:7][CH2:8][C:9]=2[O:13][N:12]=1
Reactant: CN(C)CC1CCc2onc(-c3ccccc3F)c2C1=O
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: COc1ccccc1N1CCN(CC2CCc3onc(-c4ccccc4F)c3C2=O)CC1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
To a solution consisting of 6,7-dihydro-5-dimethylaminomethyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one hydrochloride (2.40 g) in distilled water (24 ml) was added 1-(2-methoxyphenyl)piperazine hydrochloride (3.38 g) and potassium carbonate (1.02 g) at room temperature with stirring. The resulting reaction mixture was heated to reflux for 25 min. and allowed to cool to room temperature. Diethyl ether was then added and the layers separated. The aqueous phase was extracted twice with ether. The combined organics were washed with brine and dried (Na2SO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, ether) afforded 2.45 g of 6,7-dihydro-3-(2-fluorophenyl)-5-(4-(2-methoxyphenyl)-1-piperazinyl)methyl-1,2-benzisoxazol-4(5H)-one as a foam. The compound was flushed thru alumina with dichloromethane to give an oil. The maleate was prepared in ethanol and the resulting salt was washed with ether, m.p. 153°-155° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=C[CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3C(=NC=CC=3)CC2)=[N:27]C(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[N:27][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(NC2CCc3ncccc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCc3ncccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting N-(3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.49, 7.67, 7.17, 5.77, 4.55, 3.21, 3.09, 2.85–2.75, 2.58, 1.97, 1.31–1.25; HRMS (FAB) calcd for C16H19BrN4+H 347.0872, found 347.0878.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])C)([CH3:4])([CH3:3])C.[CH:12](N)([CH3:14])[CH3:13].C(N(CC)CC)C.C(Cl)(=O)C1C=CC=CC=1>>[CH:1]([NH:5][C:6](=[O:11])[C:7]1[CH:9]=[CH:14][CH:12]=[CH:13][CH:10]=1)([CH3:3])[CH3:4]
Reactant: CC(C)N
Reactant: CC(C)(C)NC(=O)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: O=C(Cl)c1ccccc1
Product: CC(C)NC(=O)c1ccccc1
Yield: 92 %

Procedure:
In a fashion similar to the preparation of LtBu,tBuH, treatment of isopropylamine (9.0 mL, 105 mmol) and triethylamine (14.9 mL, 105 mmol) with benzoyl chloride (11.72 mL, 100 mmol) afforded LPh,iPrH as white crystalline solid (15.02 g, 92%) upon crystallization of the crude product from Et2O at −20° C. followed by sublimation at 70° C./0.05 Torr: mp 101-103° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].[CH2:16]([N:18](CC)[CH2:19][CH3:20])[CH3:17].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1CCCC1>ClCCl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:18]2[CH2:19][CH2:20][CH2:17][CH2:16]2)=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(CO)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CCCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
To a solution of 4-hydroxymethyl-2-nitro-benzoic acid methyl ester (2.0 g, 9.47 mmol) in dry dichloromethane (80 mL) under argon, at room temperature, triethylamine (1.6 mL, 10.9 mmol, 1.15 eq.) and then p-toluenesulfonyl chloride (2.08 g, 10.9 mmol, 1.15 eq.) were added. The reaction mixture was stirred at room temperature for 1 h, then pyrrolidine (1.6 mL, 18.94 mmol, 2 eq.) was added and the mixture stirred for additional 24 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel, using dichloromethane-ethanol 95:5 as eluant, affording the title compound (1.12 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C@H:12]([CH3:17])[C:13]([O:15]C)=O)[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C@H:20]([OH:31])[CH2:21][N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[OH:31][C@H:20]([CH2:21][N:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30]1)[CH2:19][NH:18][C:13](=[O:15])[C@H:12]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)[CH3:17]
Reactant: COC(=O)[C@@H](C)Oc1cccc2cccnc12
Reactant: NC[C@H](O)CN1Cc2ccccc2C1
Solvent: CCO
Product: C[C@@H](Oc1cccc2cccnc12)C(=O)NC[C@H](O)CN1Cc2ccccc2C1
Temperature: 120 °C
Yield: 8.8 %

Procedure:
To a solution of (R)-methyl 2-(quinolin-8-yloxy)propanoate (100 mg, 0.433 mmol) in EtOH (1 mL) was added (S)-1-amino-3-(isoindolin-2-yl)propan-2-ol (83 mg, 0.433 mmol). The reaction mixture was heated under microwave conditions at 120° C. for 0.5 h. The mixture was concentrated and purified by preparative HPLC purification. (15 mg, yield 8.8%) MS (ESI+) e/z: 392.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 1H NMR (400 MHz, METHANOL-d4) δ 8.90 (dd, J=4.27, 1.76 Hz, 1H) 8.33 (dd, J=8.41, 1.63 Hz, 1H) 7.51-7.64 (m, 3H) 7.29 (dd, J=6.15, 2.64 Hz, 1H) 7.08-7.22 (m, 4H) 5.08 (q, J=6.78 Hz, 1H) 3.75-3.93 (m, 5H) 3.36-3.43 (m, 2H) 2.55-2.66 (m, 2H) 1.73 (d, J=6.78 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:30]=[CH:29][C:17]([O:18][CH2:19][CH2:20][P:21](=[O:28])([O:25]CC)[O:22]CC)=[CH:16][C:15]=3[CH3:31])=[CH:7][C:6]=2[C:5]2[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:4]=2[N:3]=1.C(O)(C(F)(F)F)=O>CS(C)=O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:30]=[CH:29][C:17]([O:18][CH2:19][CH2:20][P:21](=[O:22])([OH:25])[OH:28])=[CH:16][C:15]=3[CH3:31])=[CH:7][C:6]=2[C:5]2[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:4]=2[N:3]=1
Reactant: CCOP(=O)(CCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1)OCC
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCP(=O)(O)O)cc3C)cc12

Procedure:
2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethylphosphonic acid (22) was prepared according to the procedure described in Example 1—Step 3, but using diethyl 2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethylphosphonate from the previous step 2. TFA was added to the 1H NMR sample to solubilize the compound for analysis. The 1H NMR (dimethyl sulfoxide) obtained for 2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethylphosphonic acid (22) was: δ 8.83 (s, 1H), 8.71 (s, 1H), 8.35 (d, 1H, J=8.3 Hz), 7.35 (s, 1H), 7.15 (d, 1H, J=9.6 Hz), 7.08 (d, 1H, J=8.4 Hz), 7.06-7.03 (br, 2H) 6.71 (s, 1H), 6.64 (d, 1H, J=8.1 Hz), 4.09-3.99 (m, 2H), 3.07 (t, 2H, J=6.9), 2.93 (t, 2H, J=6.7), 2.44 (s, 3 H), 2.26 (s, 3H), 1.72-1.62 (m, 2H). LRMS [M+H]=452.2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: COC(CBr)OC
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1ccccc1Br)OC
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture of 2-bromophenol (34.8 ml), bromoacetaldehyde dimethyl acetal (35.5 ml), potassium carbonate (124.4 g) and dimethylformamide (500 ml) was stirred at 95° C. under nitrogen for 18 hours, then cooled and poured onto cold water (500 ml). The product was extracted into ether (2×300 ml) and the combined extracts were washed with saturated aqueous sodium bicarbonate solution (300 ml) and brine (300 ml) and dried (MgSO4). The solvent was removed in vacuo to give 2-(2-bromophenoxy) acetaldehyde dimethyl acetal as an oil (69.6 g).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13].[CH3:16][O:17]C(Cl)Cl>>[CH3:15][N:2]([CH3:1])[C:3](=[O:14])[CH2:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8]([CH3:12])=[C:9]([CH:16]=[O:17])[C:10]=1[CH3:11]
Reactant: COC(Cl)Cl
Reactant: Cc1cc(C)c(CC(=O)N(C)C)c(C)c1
Product: Cc1cc(C)c(CC(=O)N(C)C)c(C)c1C=O

Procedure:
N,N-Dimethyl-(3-formyl-2,4,6-trimethylphenyl) acetic acid amide was prepared by the formylation of N,N-dimethyl mesitylacetic acid amide with dichloromethyl methyl ether using standard conditions.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[Cl:20][C:21]1[CH:31]=[CH:30][C:24]2[S:25][CH:26]=[C:27]([CH2:28]Br)[C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH2:28][C:27]2[C:23]3[CH:22]=[C:21]([Cl:20])[CH:31]=[CH:30][C:24]=3[S:25][CH:26]=2)[C:9]2[CH:17]=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2csc3ccc(Cl)cc23)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), (5-chlorobenzo[b]-thiophen-3-yl)methylbromide (288 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.125 g (29.0%); MS m/z: 432.6 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.14 (t, 3H, 3J=7.6 Hz); 2.55 (q, 2H, 3J=7.6 Hz); 4.64 (s, 2H); 4.85 (s, 2H); 6.79 (d, 1H, 4J=2.1 Hz); 6.84 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 7.12-7.14 (m, 2H); 7.20-7.21 (m, 2H); 7.37 (d, 1H, 3J=8.9 Hz); 7.40 (dd, 1H, 4J=1.8 Hz, 3J=8.5 Hz); 7.47 (s, 1H); 7.93 (d, 1H, 4J=1.8 Hz); 7.94 (s, 1H); 8.00 (d, 1H, 3J=8.5 Hz); 12.18 (br s, 1H); HPLC (METHOD [A]): rt 19.69 min (100%)