Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[K+].[C:15]([C:17]1[N:18]=[C:19]([C:30]([O-])=[O:31])[N:20]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:21]=1)#[N:16].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCCl.CCOC(C)=O>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:30]([C:19]2[N:20]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:21]=[C:17]([C:15]#[N:16])[N:18]=2)=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: Nc1ccccc1N1CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a mixture of 2-piperidin-1-yl-phenylamine (63.5 mg, 0.360 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 100 mg, 0.327 mmol) and PyBroP (152 mg, 0.327 mmol) in 4 mL of 1,2-dichloroethane was added DIEA (171 μL, 0.981 mmol). After stirring at RT for 16 h under Ar, the mixture was treated with 50 mL of EtOAc, washed with H2O (2×10 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5-10% EtOAc/hexane) to afford 118 mg (85%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C22H31N5O2Si, 426.2 (M+H), found 426.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccccc1CBr
Reactant: NC(=O)c1cc(-c2ccc(O)cc2)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCc3ccccc3F)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.1 %

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 50 mg, 0.24 mmol), K2CO3 (37 mg, 0.27 mmol) and tetrabutylammonium iodide (9 mg, 0.024 mmol) were taken up in DMF (2.4 mL). 2-Fluorobenzyl bromide (51 mg, 0.27 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by high-throughput purification to give 3-[4-(2-fluoro-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (7.6 mg, 10%). LRMS (ESI+): m/z [2M+H]+ 625.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:28]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:29])[CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:27])[NH2:26])[CH:19]=3)=[CH:10][C:9]=2[C:37]([F:40])([F:39])[F:38])[CH2:3][CH2:2]1.[Li+].[OH-].FC(F)(F)C(O)=O>C(O)C.O>[NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:28]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:26])[NH2:27])[CH:19]=3)=[CH:10][C:9]=2[C:37]([F:38])([F:39])[F:40])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CCC(=O)N(CC=Cc1cc(C(=N)N)ccc1O)c1ccc(OC2CCNCC2)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(O)c(C=CCN(C(=O)CCC(=O)O)c2ccc(OC3CCNCC3)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl)ethylcarbonyl)-N-(3-(6-(hydroxy)-3-amidinophenyl)prop-2-en-1-yl)benzenamine (2.0 g) in 100 mL ethanol/H2O (50/50) was added LiOH (0.56 g) at ambient temperature and the resulting solution was stirred at ambient temperature for 4 hours. The reaction was acidified with trifluoroacetic acid, concentrated, separated on HPLC (CH3CN/H2O, gradient) and freeze-dried to afford 4-(piperdin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-(hydroxy)-3-amidinophenyl)prop-2-en-1-yl)benzenamine.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[N:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[S:36][N:35]=[C:34]([CH3:37])[CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[N:10][C:11]([C:32]4[S:36][N:35]=[C:34]([CH3:37])[CH:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1nc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: Cc1cc(Br)sn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1cc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)sn1
Temperature: 100 °C
Yield: 6.4 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((3-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (133.6 mg, 0.324 mmol), 5-bromo-3-methylisothiazole (69.2 mg, 0.389 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.97 mL, 0.97 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (18.7 mg, 0.016 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give white solids, 7.9 mg (yield 6.4%). 1H NMR (300 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 5.45-5.32 (m, 1H), 3.70 (m, 1H), 3.41 (t, J=9.1 Hz, 1H), 3.21 (dd, J=9.7, 6.6 Hz, 1H), 2.90-2.80 (m, 1H), 2.44 (s, 3H), 2.33 (d, J=8.8 Hz, 2H), 1.42 (d, J=6.1 Hz, 3H), 1.14 (m, 2H), 1.10-0.98 (m, 2H) ppm; MS (ESI+) m/z 384.88 (M+H).
Reaction SMILES: [C:1]([C:4](C)([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[C:5](OCC)=O)(=[O:3])[CH3:2].Cl>>[CH3:5][CH:4]([C:1](=[O:3])[CH3:2])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)CCCCCC(C)(C(C)=O)C(=O)OCC
Agent: Cl
Product: CC(=O)C(C)CCCCCC(=O)O

Procedure:
Hydrolysis of the crude diethyl 2-acetyl-2-methyl-suberate with concentrated hydrochloric acid gave a quantitative yield of 7-methyl-8-oxo-nonanoic acid.
Reaction SMILES: O[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:3]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: Cn1c(O)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1c(Cl)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Temperature: 105 °C

Procedure:
A suspension of 2-hydroxy-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (10.0 g, 30.4 mmol) and phosphorous oxychloride (250 mL, 3 mol) was heated to 105° C. for 6 h to form a solution. Monitoring reaction by HPLC showed ˜90% conversion. The reaction solution was cooled and the solvent removed under reduced pressure. Foam residue was dissolved in 500 mL 5% ethanol/chloroform. The organic layer was washed with 100 mL water three times and once with 100 mL 5% NaHCO3. Organic dried over magnesium sulfate, then dried onto 30 g of silica. Final product purified on 400 g silica eluting with 0 to 2.5% methanol/dichloromethane to give a yellow solid. M+1=348.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:11]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[CH:11]1([C:17]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([NH2:10])=[O:9])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(=O)c1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1ccccc1NC(=O)C1CCCCC1

Procedure:
Anthranilamide was treated with cyclohexanecarbonyl chloride and triethylamine in dichloromethane, followed by washing (10% citric acid; water; sat. sodium bicarbonate; and sat. sodium chloride) and evaporated to give a nearly quantitative yield of 2-(cyclohexylcarbonylamino)benzamide as a white solid, which was used immediately in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][OH:26])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:30]1[CH:34]=[CH:33][O:32][N:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:30]4[CH:34]=[CH:33][O:32][N:31]=4)[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccon1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Reaction time: 2 h
Yield: 87.2 %

Procedure:
3-(4-(4-t-Butoxycarbonyl-piperazin-1-yl)-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one (WO 93/23384; 10 g, 25.3 mmol), 3-hydroxyisoxazole (2.58 g, 30 mmol), and triphenylphosphine (9.95 g, 37.8 mmol) were dissolved in anhydrous tetrahydrofuran (300 ml), and cooled under nitrogen to 4°. Diisopropylazodicarboxylate (6.04 g, 30 mmol) was added dropwise over 10 minutes, and stirring was continued at the same temperature for 2 hours. The mixture was evaporated to dryness, and the residue purified by flash chromatography on silica, eluting with 50% EtOAc in isohexane. Relevant fractions were combined and evaporated to give the desired product (10.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20]/[C:19](=[N:23]/[OH:24])/[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1>C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20]/[C:19](=[N:23]\[OH:24])/[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N\O

Procedure:
Among the reaction product from Example 1, those fractions from the fractionation by silica gel column chromatography (ethyl acetate/hexane) that are low polarity elution fractions (demonstrating high Rf value on TLC) were collected, and the title compound (29 mg) was obtained as a colorless solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CO>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][O:18][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: OCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: N#Cc1cc([N+](=O)[O-])ccc1OCc1cccc(F)c1
Temperature: 120 °C
Yield: 80.2 %

Procedure:
A mixture of 2-fluoro-5-nitro-benzonitrile (290 m g, 1.74 mmol), 3-flouro-benzyl alcohol (1220 mg, 1.74 mmol) and K2CO3 (219 mg, 2.09 mmol) in DMA (4 ml) was heated at 120° C. for 7 h. The mixture was cooled to rt, diluted with MeOH(10 ml), filtered and purified by preparative HPLC to give 20A (380 mg, 80%).
Reaction SMILES: [H-].[K+].[CH2:3]([O:5][P:6]([CH2:11][S:12]([O:15][CH2:16][CH3:17])(=[O:14])=[O:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].Cl[CH2:19][C:20]1[C:25]([CH2:26]Cl)=[CH:24][CH:23]=[CH:22][N:21]=1>CS(C)=O>[CH2:3]([O:5][P:6]([O:8][CH2:9][CH3:10])([C:11]1([S:12]([O:15][CH2:16][CH3:17])(=[O:13])=[O:14])[CH:19]=[C:20]2[C:25]([CH:24]=[CH:23][CH2:22][NH:21]2)=[CH:26]1)=[O:7])[CH3:4]
Reactant: CCOP(=O)(CS(=O)(=O)OCC)OCC
Reactant: ClCc1cccnc1CCl
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOP(=O)(OCC)C1(S(=O)(=O)OCC)C=C2C=CCNC2=C1
Temperature: 90 °C

Procedure:
To an ice bath chilled solution of 35% potassium hydride in mineral oil (5.0 mmol) stirring under argon DMSO (7 ml) is added a solution of diethoxyphosphinyl methanesulfonic acid, ethyl ester (2.5 mmol) [prepared as described in J. C. Carretero, et. al., Tetrahedron, Vol. 43, pp. 5125-5134 (No. 21) 1987] in DMSO (5 ml). On completion of a dropwise addition, the resulting solution is stirred at room temperature for one hour. A solution of 2,3-bis(chloromethyl)pyridine (2.5 mmol) [prepared as described in K. Tsuda, et. al., Chem. Pharm. Bull., Vol.1, pp. 142, 1953] in DMSO (2 ml) is added slowly and the reaction mixture is then heated at 90° C. for 1 hour. After cooling, the reaction mixture is concentrated under reduced pressure and the desired product is purified by flash chromatography using a 5-15% isopropanol in methylene chloride gradient on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14])=O.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([Cl:24])=[N:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14]
Reactant: O=C(Nc1c(F)cncc1F)c1c(Cl)cccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: O=[N+]([O-])c1cccc(Cl)c1C(Cl)=Nc1c(F)cncc1F
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzamide (5.25 g, 16.7 mmol) in thionyl chloride (40 mL) was heated under reflux for 18 hours under a nitrogen atmosphere. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was azeotroped with toluene (×3) to afford the title compound as a yellow/brown solid (5.5 g, quantitative). LCMS (Method D): RT=3.77 min, m/z: 332 [M+H+].
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=4)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:28])[C:8]=2[N:29]=1)[CH3:2].C(#N)C>[Pt].CO>[NH2:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:13]1[CH:14]=[CH:15][C:16]2[C:7]3[N:6]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:5]([CH2:4][O:3][CH2:1][CH3:2])=[N:29][C:8]=3[C:9]([NH2:28])=[N:10][C:11]=2[CH:12]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCc4cccc([N+](=O)[O-])c4)ccc3c2n1CC(C)C
Agent: [Pt]
Solvent: CC#N
Solvent: CO
Product: CCOCc1nc2c(N)nc3cc(OCc4cccc(N)c4)ccc3c2n1CC(C)C
Yield: 9.8 %

Procedure:
2-Ethoxymethyl-1-(2-methylpropyl)-7-(3-nitrobenzyloxy)-1H-imidazo[4,5-c]quinolin-4-amine (980 mg, 2.2 mmol), prepared as described in Example 27, was mixed with acetonitrile (30 mL), and 5% platinum on carbon (˜25 mg) was added. The reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) overnight. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the presence of starting material; additional 5% platinum on carbon (˜25 mg) was added. The reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) for an additional three hours. An analysis by LC/MS again indicated that the reaction was incomplete; methanol (100 mL) and 5% platinum on carbon (200 mg) were added. The reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) overnight. The reaction mixture was filtered through a layer of CELITE filter aid, the filter cake washed with hot methanol, and the filtrate concentrated under reduced pressure to yield a solid. The solid was purified by column chromatography on silica gel (45 g, eluting with chloroform:methanol ranging in ratios from 99:1 to 95:5) to provide two products. The first product was recrystallized from 2-propanol to provide 90 mg of 7-(3-aminobenzyloxy)-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as off-white crystals, mp 228.0-230.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.CO[CH:29]1[CH:33]([CH2:34][N:35]([CH3:37])[CH3:36])[CH2:32][CH:31](OC)O1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:36][N:35]([CH2:34][C:33]1[CH:32]=[CH:31][N:1]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)[CH:29]=1)[CH3:37]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: COC1CC(CN(C)C)C(OC)O1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccc(CN(C)C)c2)cc1

Procedure:
10 millimoles of 6-(4-aminophenyl)-4,5-dihydro-5-methylpyridazinone in toluene were refluxed with 13 millimoles of toluenesulfonic acid and 12 millimoles of 2,5-dimethoxy-3-dimethylaminomethyltetrahydrofuran with the addition of a little dimethylformamide, this procedure being carried out under a water separator. When the reaction was complete, which was determined by thin layer chromatography, the major part of the solvent was stripped off, the residue was taken up in dimethylformamide and the solution was poured into saturated NaHCO3 solution. The aqueous phase was extracted with CH2Cl2 and the organic extract was dried over Na2SO4 and evaporated down in a rotary evaporator. The crude product was purified by column chromatography (SiO2, CH2Cl2 /CH3OH). 6-[4-(3-Dimethylaminomethylpyrrol-1-yl)-phenyl]-4,5-dihydro-5-methylpyridazinone was obtained, this substance being identical to that synthesized in Example 3A.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23].CCN(C(C)C)C(C)C>CN(C)C=O>[CH2:22]([N:24]([CH2:25][CH3:26])[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[CH3:23]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CCNCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)c1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) in N,N-dimethylformamide (3 mL), diethylamine (63.4 mg, 0.87 mmol, 2.00 equiv), and DIEA (170.3 mg, 1.32 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:100). This resulted in 117 mg (80%) of methyl 3-(diethylamino)-2-phenylquinoxaline-6-carboxylate as a yellow oil.
Reaction SMILES: C([CH:3]([N:7]1[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)([CH3:12])[C:10](=[O:21])[N:9](CC2C=CC(OC)=CC=2)[C:8]1=[O:31])[C:4]([O-:6])=[O:5])C.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH3:54][C:55]#N>O>[CH2:54]([O:6][C:4](=[O:5])[CH2:3][N:7]1[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)([CH3:12])[C:10](=[O:21])[NH:9][C:8]1=[O:31])[CH3:55]
Reactant: CC#N
Reactant: CCC(C(=O)[O-])N1C(=O)N(Cc2ccc(OC)cc2)C(=O)C1(C)c1cc(F)cc(F)c1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)CN1C(=O)NC(=O)C1(C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (±)-ethyl[5-(3,5-difluorophenyl)-3-(4-methoxybenzyl)-5-methyl-2,4-dioxoimidazolidin-1-yl]acetate from Step C (11.4 g, 26.3 mmol) in CH3CN (150 mL) was added drop wise a solution of ammonium cerium (IV) nitrate (43.2 g, 78.8 mmol) in water (100 mL) and the resulting mixture was stirred at ambient temperature for 3 h. The reaction was diluted with water (300 mL) and extracted with EtOAc (3×250 mL). The combined organic extracts were washed with water (50 mL), saturated NaHCO3 (50 mL), and brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the racemic title compound. The enantiomers were resolved by HPLC, utilizing a ChiralPak AD column and eluting with hexane:EtOH:DEA 40:60:1. The first major peak to elute was ethyl[5-(3,5-difluorophenyl)-5-methyl-2,4-dioxoimidazolidin-1-yl]acetate, isomer A, the title compound, and the second major peak to elute was ethyl[5-(3,5-difluorophenyl)-5-methyl-2,4-dioxoimidazolidin-1-yl]acetate, isomer B. MS: m/z=313 (M+1).
Reaction SMILES: O[C@H:2]([C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].O[C@@H](C(C)(C)C)[C@@H](NC(OCCCCCC1C=CC=CC=1)=O)C(O)=O.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@@H:2]2[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[C@@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CC(C)(C)[C@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@H]1OC(=O)[C@@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 54 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-3-hydroxy-4,4-dimethyl-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid and (2R*,3S*)-3-hydroxy-4,4-dimethyl-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid (0.325 g, 0.92 mmol) in dry CH2Cl2, (40 mL). at 0° C., Et3N (0.38 mL, 2.77 mmol) (0.2 mL, 1.44 mmol) and subsequently TBTU (0.356 g, 1.11 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 90:10 to 70:30) to afford the title compound (0.165 g, 54%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 351 [M−NH4]+; (ESI) m/z: 332 [M−H]−. 1H NMR (DMSO-d6) δ 0.94 (s, 9H), 1.29-1.39 (m, 2H), 1.52-1.65 (m, 4H), 2.58 (t, J=7.65 Hz, 2H), 4.01 (t, J=6.59 Hz, 2H), 4.33 (d, J=4.66 Hz, 1H), 4.76 (dd, J=4.65, 8.16 Hz, 1H), 7.11-7.36 (m, 5H), 8.05 (d, J=8.15 Hz, 1H).