Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:22]([CH3:33])[C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[N:11]([CH3:21])[C:12]([CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])=[CH:13][N:14]=2)=[CH:4][CH:3]=1.Br[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:19][C:16]([CH3:20])([CH2:17][CH3:18])[CH2:15][C:12]1[N:11]([CH3:21])[C:10]([CH:9]([N:22]([CH3:33])[C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=3)=[CH:3][CH:4]=2)=[N:14][CH:13]=1
Reactant: CCC(C)(C)Cc1cnc(C(Cc2ccc(Br)cc2)N(C)C(=O)OCc2ccccc2)n1C
Reactant: Fc1ccc(Br)nc1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCC(C)(C)Cc1cnc(C(Cc2ccc(-c3ccc(F)cn3)cc2)N(C)C(=O)OCc2ccccc2)n1C

Procedure:
Palladium tetrakis(triphenylphosphine) (16 mg, 0.01 mmol) was added to a degassed, ambient temperature solution of benzyl {2-(4-bromophenyl)-1-[5-(2,2-dimethylbutyl)-1-methyl-1H-imidazol-2-yl]ethyl}methylcarbamate (72 mg, 0.14 mmol), 2-bromo-5-fluoropyridine (25 mg, 0.14 mmol) and hexamethylditin (46 mg, 0.14 mmol) in 1,4-dioxane (5 mL). After stirring at reflux overnight, the reaction mixture was diluted with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded benzyl {1-[5-(2,2-dimethylbutyl)-1-methyl-1H-imidazol-2-yl]-2-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}methylcarbamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].ClC1C2C(=CC=C([CH:25]([C:27]3[N:31]([CH3:32])[C:30](C)=[N:29][CH:28]=3)O)C=2)N=C(OC)C=1CC1C=NC(C(F)(F)F)=CC=1.N1C=C(C=O)C=NC=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>N1C=CC=CC=1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH2:25][C:27]1[CH:28]=[N:29][CH:30]=[N:31][CH:32]=1)=[C:5]2[OH:13]
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=Cc1cncnc1
Solvent: c1ccncc1
Solvent: CCO
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1Cc1cncnc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a dark solution of 6-bromo-4-hydroxyquinolin-2(1H)-one (3.92 g, 16.31 mmol, Intermediate 45: step a) and pyrimidine-5-carbaldehyde (1.94 g, 17.95 mmol) in pyridine (29 mL) was added diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4.13 g, 16.31 mol). The resulting mixture was warmed with stirring in a 100° C. oil bath for a period of 5 hours. After cooling to room temperature, the mixture was diluted with ethanol. The tan precipitate was isolated by filtration, rinsing further with EtOH then acetonitrile and dried to provide the title compound that was carried to the next step without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.C(CN)O>O1CCCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[N:8]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)CN(C(=O)OC(C)(C)C)c2ccc(C(=O)OC)cc21
Solvent: C1CCOC1
Solvent: NCCO
Product: CCCCN1CCN(C(=O)OC(C)(C)C)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 37.4 %

Procedure:
A solution of 1-tert-butyl 6-methyl 4-butyl-3-oxo-3,4-dihydroquinoxaline-1,6(2H)-dicarboxylate (440 mg) and 9-BBN dimer (600 mg) in tetrahydrofuran (10 mL) was heated at 65° C. for 10 h. The mixture was cooled to room temperature, ethanolamine (0.15 mL) was added and the resulting solution was concentrated under reduced pressure. The residue was washed with hexanes, filtered, and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 ethyl acetate/hexanes) afforded 158 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.50, 7.34, 7.28, 3.88, 3.77, 3.38-3.30, 1.65-1.51, 1.42-1.34, 0.99-0.94.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:14](=[O:19])[C:15]=2[C:16](Cl)=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][NH:30][CH2:31][CH2:32][OH:33]>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:14](=[O:19])[C:15]=2[C:16]([N:30]([CH2:31][CH2:32][OH:33])[CH3:29])=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(-c2ccc(C(C)(C)C)cc2)c(C(=O)Cl)c(=O)n1-c1ccc(C#N)cc1
Reactant: CNCCO
Solvent: C1CCOC1
Product: CN(CCO)C(=O)c1c(-c2ccc(C(C)(C)C)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a liquid mixture of 150 mg of 3-(4-t-butylphenyl)-4-chlorocarbonyl-1-(4-cyanophenyl)-2-methyl-2H-pyrazol-5-one and 3 ml of tetrahydrofuran, 72 mg of N-methylethanolamine was added at room temperature, and the resulting mixture was stirred at the same temperature for another 1 hour and then concentrated under reduced pressure. After addition of 1N hydrochloric acid, the mixture was extracted with chloroform. The extract was washed with 1N hydrochloric acid and saturated aqueous sodium chloride successively and dried over anhydrous sodium sulfate. The insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized in ethyl acetate-hexane to give 110 mg of the title compound as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[Li]CCCC.[CH3:19][C:20]1([CH3:31])[C:24]([CH3:26])([CH3:25])[O:23][B:22](OC(C)C)[O:21]1>O1CCCC1>[CH3:11][C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([B:22]1[O:23][C:24]([CH3:26])([CH3:25])[C:20]([CH3:31])([CH3:19])[O:21]1)[CH:10]=2
Reactant: Cc1cc2ccc(Br)cc2[nH]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a solution of 6-bromo-2-methyl-1H-indole (2.0 g, 9.52 mmol) in dry tetrahydrofuran (100 mL) was added sodium hydride (381 mg, 9.53 mmol) with ice-cooling. After stirring for about 30 min, a solution of n-BuLi (15 mL, 2.5 M solution in hexane) was added dropwise with stirring at −78° C. under nitrogen. It was warmed slowly to −40° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −78° C. followed by dropwise addition of 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (3.54 g, 19.03 mmol). After warming to room temperature, the mixture was quenched with NH4Cl (aq) and extracted with ethyl acetate (3×80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford 2-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1.2 g, 49%).
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.Cl.[C:22]1([N:28]2[C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([NH2:37])[C:31]=3[CH:30]=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[O:19]1[C:20]2[C:12]([C:2]([CH3:1])([CH3:11])[CH2:3][C:4]([CH2:6][NH:37][C:32]3[CH:33]=[CH:34][CH:35]=[C:36]4[C:31]=3[CH:30]=[N:29][N:28]4[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([OH:5])[C:7]([F:8])([F:9])[F:10])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Reactant: Nc1cccc2c1cnn2-c1ccccc1
Agent: Cl
Product: CC(C)(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)c1cccc2c1OCC2

Procedure:
Prepared similarly to Example 7 from racemic 7-{1,1-dimethyl-2-[2-(trifluoromethyl)-2-oxiranyl]ethyl}-2,3-dihydro-1-benzofuran (which may be prepared according to WO 04/063163) and 1-phenyl-1H-indazol-4-amine hydrochloride (as the free base, Intermediate 8).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([O:13]C(=O)C)[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:17]C(=O)C)[CH:4]=1.[N-:21]=[N+]=[N-].[Na+].[Cl:25]CCl>CN(C)C=O.C(O)C>[ClH:25].[NH2:21][CH2:2][C:3]1[CH:12]=[C:11]([OH:13])[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:17])[CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1c(OC(C)=O)cc(CBr)cc1OC(C)=O
Reactant: ClCCl
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)cc(CN)cc1O
Product: Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 52 %

Procedure:
Methyl 4-bromomethyl-2,6-diacetoxybenzoate (45.8 grams, 133 mmoles) was dissolved in N,N-dimethylformamide (150 mL), and sodium azide (8.8 g, 135 mmoles) was added. The reaction mixture was stirred for 6 hours at room temperature. Dichloromethane (350 mL) was added to the reaction mixture, and this solution was washed with water (250 mL), 1M aqueous hydrochloric acid (250 mL), and saturated aqueous sodium chloride (150 mL). The organic solution was dried over anhydrous magnesium sulfate, filtered, and evaporated to a clear, pale yellow oil. The oil was dissolved in methanol (750 mL) and transferred to a 2 L Parr hydrogenation flask. Palladium on carbon catalyst (10% [w/w], 1.5 g) in water (10 mL) was added, followed by concentrated hydrochloric acid (15 mL). The flask was affixed to a Parr hydrogenator, and the mixture was shaken at room temperature under 30 psi of hydrogen for 24 hours. The reaction mixture was filtered through a 0.45 mm nylon filter. The retained solid was then washed with methanol (150 mL), and concentrated hydrochloric acid (7 mL) was added to the filtrate. The filtrate was heated to reflux for 2 hours, cooled to room temperature, and evaporated to dryness to give an off-white solid. This solid was dissolved in hot denatured ethanol (250 mL) and the solution was allowed to cool to room temperature. White crystals formed quickly. The mixture was then chilled for 16-18 hours at 4° C. to complete crystallization. The solid was filtered, washed with a little cold ethanol (50 mL) and then diethyl ether (150 mL), and dried in vacuo over potassium hydroxide pellets to afford 16.0 grams (52% yield based on monobromo starting material) of methyl 4-aminomethyl-2,6-dihydroxybenzoate hydrochloride (m.p. >260° C., open capillary, uncorrected).
Reaction SMILES: [F:1][C:2]1[C:25]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32][CH:31]=2)=[O:28])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14]C2C=CC=CC=2)=[O:12])[C@H:7]([CH3:21])[CH2:6]1.CCN(CC)CC.ClC(OC)=O>CO.[Pd]>[F:1][C:2]1[C:25]([NH:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][N:33]=[C:34]([CH3:36])[CH:35]=2)=[O:28])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH3:14])=[O:12])[C@H:7]([CH3:21])[CH2:6]1
Reactant: Cc1cc(NC(=O)Nc2cccc(CN3CCN(C(=O)OCc4ccccc4)[C@H](C)C3)c2F)ccn1
Agent: [Pd]
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)N1CCN(Cc2cccc(NC(=O)Nc3ccnc(C)c3)c2F)C[C@H]1C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of (R)-benzyl 4-(2-fluoro-3-(3-(6-methylpyridin-4-yl)ureido)benzyl)-2-methylpiperazine-1-carboxylate (190 mg, 0.39 mmol, 1.0 equiv) in MeOH (20 mL) was added 10% Pd/C (approx. 100 mg). The resulting suspension was stirred and sparged with hydrogen gas using a balloon and needle. After 1 h, reaction was complete, as determined by LCMS. The mixture was filtered through a pad of Celite, and the celite pad was washed with additional methanol. The mixture was concentrated in vacuo, and the resulting residue was dissolved in dry DCM (10 mL). To this room temperature solution was added Et3N (167 uL, 1.2 mmol, 3.0 equiv), followed by the addition of methyl chloroformate (46 uL, 0.60 mmol, 1.5 equiv) by syringe. After 10 minutes the reaction mixture was quenched by the addition of methanol. The solvent was removed in vacuo, and the mixture was purified by preparative TLC (0.5% Et3N/7% MeOH/92.5% DCM) to provide (R)-methyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)-2-methylpiperazine-1-carboxylate (85.9 mg, 50%). LCMS m/z (APCI)=416.3 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(N2C3C=CC(C4NN=NN=4)=CC=3OC3C2=CC=CC=3)CC1)=O)(C)(C)C.[C:66]([OH:72])([C:68]([F:71])([F:70])[F:69])=[O:67].Cl>C(Cl)Cl>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:13]1.[C:66]([OH:72])([C:68]([F:71])([F:70])[F:69])=[O:67]
Reactant: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4cccnc4)ccc32)CC1
Agent: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4nnn[nH]4)ccc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(-c2ccc3c(c2)Oc2ccccc2N3C2CCNCC2)c1

Procedure:
Using an adaptation of the method described in Procedure 6, substituting 4-(3-pyridin-3-yl-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 3i, for 4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 5a, and a mixture of TFA in methylene chloride for a 4N hydrochloric acid solution, the title compound 10-piperidin-4-yl-3-pyridin-3-yl-10H-phenoxazine, 4i was obtained as a TFA salt after purification via reverse phase HPLC (eluent gradient: CH3CN in water containing 0.1% TFA). MS m/z (MH+) 344.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH2:29]([N:31]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH3:30].C(OCC)(=O)C>CN(C=O)C>[Cl-:1].[CH2:29]([N+:31]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH3:30]
Reactant: CCN1CCCCCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[N+]1(Cc2ccc(NC(=O)C3=Cc4cc(-c5ccc(C)cc5)ccc4CC3)cc2)CCCCCC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.8 %

Procedure:
In DMF (3 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the mixture was added 1-ethylperhydroazepine (98 mg). The mixture was stirred at room temperature for 15 hours. To the reaction mixture was added ethyl acetate (100 ml), and the resulting precipitate was filtered and recrystallized from ethyl acetate-methanol to give 1-ethyl-1-[4-[7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamido]benzyl]perhydroazepinium chloride (Compound 37) (137 mg) as colorless crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH:12]([CH3:36])[C:13]([NH:15][CH:16]1[C:22](=[O:23])[N:21]([CH3:24])[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=2[C:18]([C:29]2[CH:34]=[CH:33][C:32](F)=[CH:31][CH:30]=2)=[N:17]1)=[O:14])(=[O:10])=[O:9].[F:37][C:38]([F:50])([F:49])C1C=CC=CC=1S(Cl)(=O)=O>>[CH3:24][N:21]1[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=2[C:18]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:17][CH:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:38]([F:50])([F:49])[F:37])(=[O:10])=[O:9])[CH3:36])[C:22]1=[O:23]
Reactant: CC(NS(=O)(=O)c1ccccc1F)C(=O)NC1N=C(c2ccc(F)cc2)c2ccccc2N(C)C1=O
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Product: CC(NS(=O)(=O)c1ccccc1C(F)(F)F)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Yield: 68 %

Procedure:
The compound of Example 53 was synthesized in a procedure analogous to the synthesis of the compound of Example 52 using 2-trifluoromethyl benzene sulfonyl chloride in 68% yield. MS (ESI) M+H=545.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](Cl)=[O:15])=[C:12]([CH3:17])[O:11][N:10]=1.[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:19].C(N(CC)CC)C>ClCCl>[CH3:17][C:12]1[O:11][N:10]=[C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:13]=1[C:14]([NH:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([O:20][CH2:18][CH3:19])=[O:29])=[O:15]
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cccc(NC(=O)c2c(-c3c(F)cccc3Cl)noc2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(2-Chloro-6-fluorophenyl)5-methylisoxaz-4-oyl chloride (7.9 g, 29.0 mmol) was added in portions to a stirred solution of ethyl-3-aminobenzoate (4.0 g, 29.0 mmol) and triethylamine (4.04 mL, 29.0 mmol) in dry dichloromethane at 0° C. Following the final addition, the mixture was allowed to warm to ambient temperature and stir for 1 hour. The solution was washed with 0.5M aqueous hydrochloric acid, brine, aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated to a foam which was used in subsequent reactions without further purification.
Reaction SMILES: [C:1]([NH2:7])([NH2:6])=[N:2][C:3]([NH2:5])=[NH:4].CN=[C:10]=[S:11].[CH3:12]N(C)C=O>>[NH2:6][C:1]1[N:2]=[C:3]([NH2:5])[N:4]([CH3:12])[C:10](=[S:11])[N:7]=1
Reactant: CN=C=S
Reactant: CN(C)C=O
Reactant: N=C(N)N=C(N)N
Product: Cn1c(N)nc(N)nc1=S
Temperature: 100 °C

Procedure:
To 12 of dry dimethylformamide were dissolved 1.52 g of diguanide and 1.1 g of methylisothiocyanate, and the solution was heated at 100° C. for 30 minutes to produce white precipitates. After filtering off the precipitates rapidly, the filtrate was added to 500 ml of ice water to produce precipitates, which was subsequently filtered and recrystalized with 25 ml of 50% ethanol to obtain 2 g of the title compound having the characteristics of:
Reaction SMILES: [OH:1][C@@H:2]1[CH:6]([OH:7])[CH:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[O:4][C@H:3]1[N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([N:37]1[CH2:41][CH2:40][C@@H:39]([NH:42][C:43]([NH:45][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=3)=[O:44])[CH2:38]1)=[N:17][C:18]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C:52](=[O:55])([O-])[O-].[K+].[K+].[CH3:58]N(C=O)C>>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([C:8]2[N:12]=[N:11][N:10]([CH2:58][CH2:52][OH:55])[N:9]=2)[O:4][C@H:3]1[N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([N:37]1[CH2:41][CH2:40][C@@H:39]([NH:42][C:43]([NH:45][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=3)=[O:44])[CH2:38]1)=[N:17][C:18]=2[NH:22][CH2:23][CH:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CN(C)C=O
Reactant: O=C(Nc1cccnc1)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4OC(c5nn[nH]n5)C(O)[C@H]4O)c3n2)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: O=C(Nc1cccnc1)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4O[C@H](c5nnn(CCO)n5)[C@@H](O)[C@H]4O)c3n2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-{(R)-1-[9-[(2R,3R,4S R)-3,4-dihydroxy-5-(2H-tetrazol-5-yl)-tetrahydro-furan-2-yl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-3-pyridin-3-yl-urea in DMF is treated with potassium carbonate followed by 3-bromoethanol and stirred at RT for 18 hours. The mixture is then filtered and the filtrate is concentrated in vacuo. Purification of the crude product by C-18 reverse phase column chromatography eluting with acetonitrile:water (0.1% TFA) (gradient 0-100% acetonitrile) to affords the titled compound.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([N:28]4[CH2:32][CH2:31][NH:30][C:29]4=[O:33])[CH:25]=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)[N:5]=1.[H-].[Na+].I[CH:37]([CH3:39])[CH3:38]>CN(C=O)C>[ClH:1].[ClH:1].[CH3:38][CH:37]([N:30]1[CH2:31][CH2:32][N:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][CH2:20][N:17]3[CH2:18][CH2:19][N:14]([C:10]4[CH:9]=[CH:8][CH:7]=[C:6]5[C:11]=4[CH:12]=[CH:13][C:4]([CH3:3])=[N:5]5)[CH2:15][CH2:16]3)[CH:23]=2)[C:29]1=[O:33])[CH3:39]
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N5CCNC5=O)c4)CC3)cccc2n1
Reactant: CC(C)I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCN(C(C)C)C5=O)c4)CC3)cccc2n1

Procedure:
The title compound was prepared according to the procedure described for Example 156 using 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (Example 85, 50 mg), DMF (1 mL), sodium hydride (60%, 10 mg) and 2-iodopropane (13 μL). Yield 17 mg.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH:19][C:20]2[C:21](=[O:33])[N:22]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([Cl:26])=[CH:24][N:25]=2)[CH2:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:43][S:44]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH:19][C:20]2[C:21](=[O:33])[N:22]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([Cl:26])=[CH:24][N:25]=2)[CH2:9]1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cn1c(Cl)cnc(N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccccn2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cn1c(Cl)cnc(N[C@@H]2CN(S(C)(=O)=O)C[C@H]2c2ccccn2)c1=O
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred solution of the hydrochloride salt of 3-(trans-4-(2-pyridyl)-pyrrolidin-3-ylamino)-6-chloro-1-ethoxycarbonylmethylpyrazinone from step 9 above (0.2 g, 0.48 mmol) in CH2Cl2 (20 mL) at 0° C. was added DIEA (0.30 mL, 1.7 mmol) and methanesulfonyl chloride (63 mg, 0.55 mmol). The resulting solution was stirred at 0° C. for 6 h and then at ambient temperature for 12 h. The mixture was diluted with CH2Cl2 and aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography using a gradient elution of 2-4% MeOH:CH2Cl2 (0.20 g, TLC Rf=0.5, 95:5 CH2Cl2:MeOH; HPLC RT=5.47 min, method A).