Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.C([NH:39][C:40]([CH3:45])([C:42](O)=[O:43])[CH3:41])(OC(C)(C)C)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C.CO.CS(C)=O>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH2:3][NH:2][C:42](=[O:43])[C:40]([CH3:45])([CH3:41])[NH2:39])[CH:9]=[CH:8][CH:7]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)C(C)(C)N)c1
Reaction time: 8 h
Yield: 42 %

Procedure:
A mixture of N-[1′-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see intermediate 4) (529 mg, 1.06 mmol), N—BOC-alpha-methylalanine (Sigma) (248 mg, 1.22 mmol), HATU (503 mg, 1.32 mmol) was stirred in DMF (2 mL) and DIPEA (0.75 mL, 4.4 mmol) until the mixture dissolved and then stood overnight at room temperature. The mixture was then treated with TFA (1.5 mL, 19.5 mmol) at room temperature and after 45 min more TFA (1.5 mL, 19.5 mmol) added. After 1.5 h more TFA (1 mL) was added and the mixture was stirred for 18 h. The mixture was concentrated under reduced pressure and the residue was loaded in methanol and purified by SPE on ion exchange cartridge (SCX-2) 50 g eluting with MeOH, followed by 10% aqueous ammonia in MeOH. The appropriate ammoniacal fractions were combined and evaporated in vacuo to give the crude product. The sample was dissolved in 1:1 MeOH-DMSO 8 mL and purified by Mass Directed AutoPrep on Xbridge column using Acetonitrile Water with an ammonium carbonate modifier (Method C) collecting the peak with RT˜6.0 min. The solvent was evaporated in vacuo to give the title compound (242 mg, 42%): LCMS (System C) RT=2.01 min, ES+ve m/z 548/550 (M+H)+; NMR δ (CD3OD) 7.26-7.13 (4H, m), 7.10 (1H, br d, J 7 Hz), 7.05 (1H, br s), 6.92 (1H, d, J 8 Hz), 6.86 (1H, d, J 4 Hz), 6.40 (1H, d, J 8 Hz), 5.45 (2H, s), 4.31 (2H, s), 3.77 (3H, s), 1.31 (6H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH2:14]>O1CCOCC1.C(N(CC)C(C)C)(C)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:11]([Cl:10])[CH:12]=2)[N:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1cc(Cl)nc(Nc2ccc(Cl)c(Cl)c2)n1
Reaction time: 3 h
Yield: 21.7 %

Procedure:
A solution of 2,4,6-trichloropyrimidine (5.00 g), 3,4-dichloroaniline (4.45 g, 1 equivalent) in 1,4-dioxane (20 mL) and N,N-diisopropylethylamine (10 mL) was heated at reflux with stirring for 3 hours. The solvent was removed and the crude material was purified by flash chromatography on silica gel. The column was eluted with a gradient of cyclohexane to ethyl acetate/cyclohexane (1:9). The eluent was removed, giving 4,6-dichloro-N-(3,4-dichlorophenyl)-2-pyrimidinamine (1.83 g, 58%, Rf=0.39 in ethyl acetate/cyclohexane, 2:3).
Reaction SMILES: [Cl-].[NH4+].O.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14])=[C:7]([N+:16]([O-])=O)[CH:6]=1>C(O)C.[Fe]>[NH2:16][C:7]1[CH:6]=[C:5]([Br:4])[CH:10]=[CH:9][C:8]=1[NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14]
Reactant: C[C@@H](CO)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C[C@@H](CO)Nc1ccc(Br)cc1N
Temperature: 80 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
A 2-L, three-necked, round bottomed flask fitted with a nitrogen inlet, overhead stirrer, thermocouple, and condenser was charged with iron power (117 g, 2090 mmol), ammonium chloride (1.118 g, 20.90 mmol), ethanol (375 mL), and water (201 mL). The mixture was heated to 80° C., and a solution of (S)-2-(4-bromo-2-nitrophenylamino)propane-1-ol (57.5 g, 209 mmol) in ethanol (200 mL) was slowly added. The mixture stirred at 80° C. for 4 h. The reaction mixture was filtered through a pad of Celite and washed with ethanol (100 mL). The filtrate was concentrated under reduced pressure to remove the ethanol, and the resulting aqueous slurry stirred at rt for 3 h. The slurry was then filtered, and the solids were washed with water (100 mL) and dried under a nitrogen atmosphere overnight to afford (S)-2-(2-amino-4-bromophenylamino)propane-1-ol (47.55 g, 89%) as an off-white solid. MS (ESI, pos. ion) m/z 245 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]=[CH:21][C:22]4[S:23][C:24]([Cl:27])=[CH:25][CH:26]=4)[C@@H:15]([CH3:28])[C:14]3=[O:29])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.C([O-])(=O)C.[NH4+:41]>>[NH2:41][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]=[CH:21][C:22]4[S:23][C:24]([Cl:27])=[CH:25][CH:26]=4)[C@@H:15]([CH3:28])[C:14]3=[O:29])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1C(=O)N(Cc2ccc3c(Cl)ccnc3c2)CCN1CC=Cc1ccc(Cl)s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Oc1ccccc1
Product: C[C@H]1C(=O)N(Cc2ccc3c(N)ccnc3c2)CCN1CC=Cc1ccc(Cl)s1
Temperature: 120 °C
Yield: 42.7 %

Procedure:
(S)-1-(4-Chloroquinolin-7-ylmethyl)-4-[3-(5-chlorothiophen-2-yl)-allyl]-3-methylpiperazin-2-one(0.35 g, 0.82 mmol) is treated with phenol (2 g) and ammonium acetate (0.7 g, 9.1 mmol) and heated to 120° C. in a sealed vessel for 1 hour. Upon cooling, the solution is partitioned between 2 N NaOH and ethyl acetate. The organic layer is separated and washed with fresh 2 N NaOH (3×100 mL) and water. The organic layer is concentrated and the residue is purified by reverse phase HPLC to give the title compound as a white solid (0.15 g, 0.35 mmol). MS (ISP) m/z 427, 429, (M+H), Cl pattern.
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:9]1([C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][O:11]1)=[O:10].O>C(O)C>[C:1]([NH:5][NH:6][C:9](=[O:10])[C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:12][OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1OCc2ccccc21
Reactant: CC(C)(C)NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NNC(=O)c1ccccc1CO
Yield: 13.5 %

Procedure:
t-Butylhydrazine (0.1 mol) in 75 ml ethanol was treated with 50% aqueous sodium hydroxide (0.11 mol). Phthalide (0.1 mol) was added and the mixture was refluxed for 5 days. After cooling, water was added and the crude product was isolated by filtration. Filtration through silica gel afforded N'-t-butyl-N-(2-hydroxymethylbenzoyl)hydrazine (3.0 g): m.p. 116°-118° C.
Reaction SMILES: C(O)C.C(=O)(O)O.[NH2:8][C:9]([NH2:11])=[NH:10].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O>O>[NH2:10][C:9]1[NH:11][C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[N:8]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: O
Solvent: CCO
Product: Cc1cc(=O)[nH]c(N)n1
Temperature: 25 °C
Yield: 68 %

Procedure:
The above compound was prepared according to a literature method (Hirschberg, J. H. K., Beijer, F. H., van Aert, H. A., Magusin, P. C. M., Sijbesma, R. P., Meijer, E. W., Macromolecules, 1999, 32, 2696-2705, the disclosure of which is totally incorporated herein by reference). To a 1 liter round bottom flask under an inert argon atmosphere was added 650 milliliters of dry ethanol and 90.08 grams (0.5 mole) of guanidine carbonate. Thereafter, with good stirring was added dropwise over 2 hours 130.17 grams (1 mole) of ethyl acetoacetate, after which heat was applied and the mixture refluxed for 15 hours. The mixture was then cooled to room temperature and 800 milliliters of deionized water was slowly added to induce precipitation of the product. Subsequent vacuum filtration and washing with cold acetone secured the anticipated product in 68 percent yield (mp 311° C.). All physical properties were in accord with the reported properties.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16]CC2C=CC=CC=2)[C:10]=1[C:24](=[O:26])[CH3:25])C1C=CC=CC=1.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[CH:37]=O>>[OH:16][C:11]1[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([OH:8])[C:10]=1[C:24](=[O:26])[CH2:25][CH2:37][C:28]1[CH:29]=[CH:30][C:31]2[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=2[CH:27]=1
Reactant: CC(=O)c1c(OCc2ccccc2)cc(C)cc1OCc1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Product: Cc1cc(O)c(C(=O)CCc2ccc3c(c2)CCCC3)c(O)c1

Procedure:
The intermediate, 1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone, was treated with 2-naphthaldehyde as described in Example 1, Part B. Subsequent catalytic hydrogenation as described in Example 1, Part C, provided 1-(2,6-Dihydroxy-4-methyl-phenyl)-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-1 -one as a by-product. Further treatment of this by-product as described in Example 1, Part D and E, afforded the title compound. 1HNMR (400 MHz, CD3OD) δ 7.02 (s, 1H), 6.93 (m, 2H), 6.87 (s, 1H) 6.61 (s, 1H), 5.24 (d, J=7.73 Hz, 1H), 3.94 (d, J=12.05 Hz, 1H), 3.75-3.34 (m, 5H), 3.25-2.72 (m, 8H), 2.43 (s, 3H), 1.81-1.77 (m, 4H). MS: m/z (MH+) 469.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:22]=[CH:21][C:20](OC)=[N:19][C:10]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Cl:27][C:20]1[CH:21]=[CH:22][C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:14][CH2:13][C:12]3[O:15][N:16]=[C:17]([CH3:18])[C:11]=3[C:10]=2[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(n1)-c1c(C)noc1CN=C2c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1noc2c1-c1nc(Cl)ccc1C(c1ccc(Cl)cc1)=NC2
Temperature: 140 °C

Procedure:
To 5-(4-chlorophenyl)-2-methoxy-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine (0.050 g, 0.147 mmol) were added phosphoryl chloride (1 mL, 11 mmol) and DMF (0.1 mL) at room temperature. The reaction was heated to 140° C. for 4 h using microwave irradiation before 2M aq. NaOH and 2M aq. Na2CO3 were added to quench the excess of reagent. The desired product was extracted using EtOAc (repeated 4 times). The organic layers were combined, dried over Na2SO4 and concentrated to dryness. A fraction of the residue was purified by reverse phase chromatography to give the title product as a white solid. LC/MS m/z 344 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J=8.52 Hz, 1H), 7.49 (d, J=8.31 Hz, 1H), 7.46 (td, J=2.10, 8.70 Hz, 2H), 7.41 (td, J=2.10, 8.70 Hz, 2H), 4.80 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](=O)[CH3:4].[C:7]([NH:10][C:11]([NH2:13])=[NH:12])(=[O:9])[CH3:8]>CN(C=O)C>[CH3:4][C:3]1[N:12]=[C:11]([NH:10][C:7](=[O:9])[CH3:8])[NH:13][C:2]=1[CH3:6]
Reactant: CC(=O)C(C)Br
Reactant: CC(=O)NC(=N)N
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(C)[nH]1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A dry round bottom flask was charged with a 0.3 M (20.0 mmol) solution of 3-bromobutan-2-one. Acetylguanidine (60.0 mmol) in dry DMF was added to the mixture. The mixture was stirred at room temperature for 96 hours. The solvent was evaporated off and the residue was washed with water, filtered, dried and recrystallized with methanol to give crude N-(4,5-dimethyl-1H-imidazol-2-yl)acetamide. This material was suspended in 100 mL of 1:1 MeOH:H2O solution with 1.5 mL of H2SO4, and heated to reflux for 16 hours (overnight). The reaction mixture was then allowed to cool to room temperature and concentrated at reduced pressure. The resulting crude material was treated with ethanol and ether, treated in an ultrasonic bath and concentrated at reduced pressure. The crude product was further purified by silica column chromatography (starting with 5% MeOH in dichloromethane, in increments of 5% to 35% MeOH in dichloromethane) to give 609 mg of 4,5-dimethyl-1H-imidazol-2-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][NH:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[C:26]1([O:25][C:23](=[O:24])[N:11]([CH2:10][CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:12]([CH3:14])[CH3:13])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)NCCSc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(CCSc1ccc(Cl)cc1)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of 22.8 g (0.1 mole) of N-[2-[(4-chlorophenyl)thio]ethyl]-1-methylethanamine (oil in Preparation 1) and 10.1 g (0.1 mole) of triethylamine in 300 ml of methylene chloride was added dropwise with stirring a solution of 15.7 g (0.1 mole) phenyl chloroformate in 100 ml of methylene chloride. The resulting solution was stirred overnight at room temperature. The methylene chloride layer was extracted with 5% sodium hydroxide solution followed by 1N sulfuric acid. The methylene chloride layer was concentrated to give an oil which crystallized to a white solid. Recrystallization from isopropyl ether gave white crystalline product, m.p. 54°-56° C. in 79.6% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([NH2:13])[CH:10]=[N:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:2]=1.Br[C:21]1[S:22][CH:23]=[CH:24][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([NH:13][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)[CH:10]=[N:9][C:8]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[CH:2]=1
Reactant: Nc1cnc(-c2ccncc2)c(-c2cccnc2)n1
Reactant: Brc1nccs1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: c1cncc(-c2nc(Nc3nccs3)cnc2-c2ccncc2)c1
Reaction time: 16 h
Yield: 43.7 %

Procedure:
An oven dried resealable Schlenk tube was charged with 6-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-amine (Example 13, 60 mg, 0.241 mmol), 2-bromo-1,3-thiazole (22 μL, 0.241 mmol), cesium carbonate (110 mg, 0.337 mmol) and dioxane (2.5 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and tris(dibenzylideneacetone)dipalladium(0) (9 mg, 0.01 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (11 mg, 0.019 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 100° C. oil bath. After 16 h, the mixture was cooled, partitioned between water and ethyl acetate, the aqueous phase was extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. Flash chromatography (95:5 dichloromethane/methanol) furnished the title compound as a solid (35 mg, 44%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:29]1[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 89.1 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate (27 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 34 mg of the titled compound (yield, 88%). 1H NMR (300 MHz, CDCl3): δ 3.29 (s, 4H), 3.77 (s, 3H), 4.14 (s, 4H), 6.89-6.97 (m, 4H), 7.24-7.56 (m, 5H), 7.62-7.71 (m, 1H)
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[NH:12][N:13]=[C:14]([S:16][CH3:17])[N:15]=2)[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])[CH3:3].C1C=C([O:29]O)C(C(O)=O)=C(C(O)=O)C=1>C(O)C.O>[CH3:19][C:18]([C:7]1[CH:8]=[C:9]([C:11]2[NH:12][N:13]=[C:14]([S:16]([CH3:17])=[O:29])[N:15]=2)[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: CSc1n[nH]c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Solvent: O
Solvent: CCO
Product: CS(=O)c1n[nH]c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Reaction time: 2 h
Yield: 30 %

Procedure:
A 50° C. solution of 1.0 g (3.13 mmol) of the methylthiotriazole (Example 43) in 50 ml of 95% ethanol is treated dropwise with a solution of 0.92 g (2.98 mmol) of 80% monoperoxyphthalic acid, magnesium salt (MMPP) in 4.5 ml of water over 20 minutes. The resulting reaction mixture is stirred at 40° to 50° C. for two hours and concentrated in vacuo. The residue is dissolved in ethyl acetate, extracted with saturated aqueous NaHCO3 (three times), water and brine, dried over Na2SO4 and concentrated in vacuo. Flash chromatography (SiO2, 5% methanol-chloroform, 26×6.5 cm) followed by recrystallization from acetone-water gives 0.30 g (1.05 g theor., 29%) of the sulfoxide as a white solid, mp 135°-145° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[C:14]([CH3:21])[CH:13]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:36]Br>C1COCC1.[NH4+].[Cl-]>[F:32][C:33]1[CH:34]=[C:35]([CH2:36][CH:18]([C:15]2[CH:16]=[CH:17][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:13][C:14]=2[CH3:21])[C:19]#[N:20])[CH:38]=[C:39]([F:41])[CH:40]=1
Reactant: COCCCc1ccccc1-c1ccc(CC#N)c(C)c1
Reactant: Fc1cc(F)cc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCCc1ccccc1-c1ccc(C(C#N)Cc2cc(F)cc(F)c2)c(C)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of [2′-(3-methoxypropyl)-3-methylbiphenyl-4-yl]acetonitrile (1.2 eq.) from step 1 in THF (0.02M) at −78° C. was added lithium hexamethyldisilazide (LiHMDS; 1.3 eq.). The reaction mixture was stirred 15 min at −78° C. To the resulting solution was cannulated a solution of 3,5-difluorobenzyl bromide (1 eq.) in THF (0.04M). The final mixture was allowed to warm slowly to room temperature and then stirred and extra 4 h. The resulting mixture was poured in saturated aqueous NH4Cl and extracted with EtOAc. The organic extract was dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 50% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: CN([CH:4]=[CH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16]C)=[O:14])=[CH:9][CH:8]=1)C.Cl.[CH2:20]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[NH:32])=[CH:29][CH:28]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C[O-].[Na+]>CO>[CH2:20]([O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]2[N:33]=[CH:4][CH:5]=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=3)[N:32]=2)=[CH:34][CH:35]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCOC(=O)c1ccc(C(=O)C=CN(C)C)cc1
Reactant: CCCCCCOc1ccc(C(=N)N)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCCOc1ccc(-c2nccc(-c3ccc(C(=O)OC)cc3)n2)cc1
Yield: 52.1 %

Procedure:
To a suspension of 1-(N,N-dimethylamino)-2-(4-ethoxycarbonylbenzoyl)ethylene (0.742 g) and 4-n-hexyloxybenzamidine hydrochloride (0.847 g) in methanol (10 ml) was added 28% sodium methoxide in methanol (0.64 ml). The suspension was refluxed for 6 hours, and partitioned with ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with acetonitrile, collected by filtration and dried under reduced pressure to give Methyl 4-[2-(4-n-hexyloxyphenyl)pyrimidin-6-yl]benzoate (0.61 g).
Reaction SMILES: [OH:1][C@H:2]([C:27]1[C:28]([CH3:37])=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[O:31][CH2:30]2)[CH2:3][N:4]1[CH:9]2[CH2:10][N:11]([CH2:13][CH2:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[C:21](=[O:25])[O:20][C@H:19]([CH3:26])[CH2:18]4)[CH2:12][CH:5]1[CH2:6][O:7][CH2:8]2.O[C@H](C1C=CC2C(=O)OCC=2C=1C)CN1C2CNCC1COC2.C[C@H]1CC2C(=CC=C(CC=O)C=2)C(=O)O1>>[OH:1][C@H:2]([C:27]1[C:28]([CH3:37])=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[O:31][CH2:30]2)[CH2:3][N:4]1[CH:5]2[CH2:12][N:11]([CH2:13][CH2:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[C:21](=[O:25])[O:20][C@@H:19]([CH3:26])[CH2:18]4)[CH2:10][CH:9]1[CH2:8][O:7][CH2:6]2
Reactant: Cc1c([C@@H](O)CN2C3COCC2CN(CCc2ccc4c(c2)C[C@@H](C)OC4=O)C3)ccc2c1COC2=O
Agent: C[C@H]1Cc2cc(CC=O)ccc2C(=O)O1
Agent: Cc1c([C@@H](O)CN2C3CNCC2COC3)ccc2c1COC2=O
Product: Cc1c([C@@H](O)CN2C3COCC2CN(CCc2ccc4c(c2)C[C@H](C)OC4=O)C3)ccc2c1COC2=O

Procedure:
(S)-6-(2-(9-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)ethyl)-3-methylisochroman-1-one was prepared in an analogous fashion to that described for the synthesis of (R)-6-(2-(9-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)ethyl)-3-methylisochroman-1-one (EXAMPLE 21) starting from 5-[(1R)-1-hydroxy-2-(3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)ethyl]-4-methyl-2-benzofuran-1 (3H)-one (INTERMEDIATE 17) and (S)-2-(3-Methyl-1-oxoisochroman-6-yl)acetaldehyde (INTERMEDIATE 22).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:32])[N:4]([C:21]2[CH:26]=[C:25]([C:27](=O)[C:28]#[CH:29])[CH:24]=[CH:23][C:22]=2[CH3:31])[C:5]([CH3:20])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=1.Cl.[OH:34][C:35]([CH3:40])([CH3:39])[C:36]([NH2:38])=[NH:37].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:32])[N:4]([C:21]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][N:38]=[C:36]([C:35]([OH:34])([CH3:40])[CH3:39])[N:37]=3)[CH:24]=[CH:23][C:22]=2[CH3:31])[C:5]([CH3:20])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=1
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C(F)(F)F)n3)c(Cl)c2=O)c1
Reactant: CC(C)(O)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(OCc2cccc(C(F)(F)F)n2)c(Cl)c1=O
Temperature: 75 °C
Yield: 31.6 %

Procedure:
To a solution of 5-chloro-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-6-(6-trifluoromethyl-pyridin-2-ylmethoxy)-3H-pyrimidin-4-one of Step C (50 mg, 0.11 mmol) in acetonitrile (1 mL) was added 2-hydroxy-2-methylpropionamidine HCl (23 mg, 0.16 mmol) and potassium carbonate (45 mg, 0.33 mmol) and the slurry heated at 75° C. for eighteen hours. After cooling to room temperature the reaction was filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a yellow oil (19 mg, 32% yield). MS (M+H): 546; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.15 (s, 3H), 2.21 (s, 3H), 5.69-5.78 (m, 2H), 7.56-7.59 (m, 2H), 7.66 (d, J=7.43 Hz, 1H), 7.82 (d, J=7.82 Hz, 1H), 7.94-8.00 (m, 2H), 8.14 (d, J=7.43 Hz, 1H), 8.78 (d, J=5.08 Hz, 1H).