Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[H-].[Na+].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(OCC)(=O)C>CN(C)C=O.O>[NH2:1][C@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH:5]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(C[C@H](N)C(=O)OCc3ccccc3)c3ccccc32)cc1
Reaction time: 0.33 h

Procedure:
In N,N-dimethylformamide (DMF) (10 ml) was dissolved Tr-Trp-OBzl (2.15 g, 4 mM), followed by addition of sodium hydride (50% in mineral oil, the same applies below; 240 mg, 5 mM) in a nitrogen gas stream. The reaction was conducted at room temperature for 20 minutes, after which p-toluenesulfonyl chloride (950 mg, 5 mM) was added. The reaction was further carried out at room temperature for 15 hours, at the end of which time ethyl acetate (50 ml) was added and the mixture was stirred for one hour. To the reaction mixture was added water (30 ml) with caution and the organic layer was taken and washed with 5% aqueous sodium hydrogen carbonate and water. After drying over sodium sulfate, the ethyl acetate was distilled off. The residue was purified by column chromatography on silica gel (15 g) using toluene as the solvent to give Tr-Trp(Tos)-OBzl. Yield 1.70 g (61.5%); m.p. 101°-103° C.; [α]D24 +47.6° (c=0.5, DMF).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:17][OH:18])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([OH:12])=O.ClC1N=C(COC)NC=1C1C=C(C=CC=1C)C(O)=O.Cl.[F:39][C:40]1([C:44]2[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=2)[CH2:43][NH:42][CH2:41]1.Cl.N1CCC(C2C=CC(C#N)=CC=2)CC1>>[Cl:1][C:2]1[N:3]=[C:4]([CH2:17][OH:18])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([N:42]1[CH2:41][C:40]([C:44]2[CH:45]=[CH:46][C:47]([C:48]#[N:49])=[CH:50][CH:51]=2)([F:39])[CH2:43]1)=[O:12]
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(CO)nc1Cl
Agent: COCc1nc(Cl)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CCNCC2)cc1
Product: Cc1ccc(C(=O)N2CC(F)(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(CO)nc1Cl

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 27, except 3-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 28.1) was used in place of 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 27.5) and 4-(3-Fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) was used in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 425 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([CH3:8])[C:4]([O:6]C)=[O:5].[C:12](#[N:14])[CH3:13]>>[F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([CH3:8])[C:4](=[O:5])[CH2:13][C:12]#[N:14].[F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([CH3:8])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(C)(C)C(F)(F)F
Reactant: CC#N
Product: CC(C)(C(=O)CC#N)C(F)(F)F
Product: CC(C)(C(=O)O)C(F)(F)F
Temperature: 70 °C

Procedure:
Reaction was carried out in two separate batches, employing 3.85 g of methyl 3,3,3-trifluoro-2,2-dimethylpropanoate in each batch. To a stirred refluxing suspension of sodium hydride (1.41 g of a 60% dispersion in mineral oil, 35 mmol) in dry THF (30 mL) (under an argon atmosphere) was added a mixture of crude methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (3.85 g) and dry acetonitrile (1.85 mL, 35 mmol), dropwise over the course of 45 mins. The resulting pale yellow suspension was heated at 70° C. for a further 15 h. After cooling to rt, both reaction batches were combined whereupon the solvent was removed in vacuo. The resulting orange foam was redissolved in water (200 mL) and washed with diethyl ether (2×200 mL), to remove residual mineral oil. The aqueous layer was separated, acidified to pH 2 with aqueous 2N hydrochloric acid and extracted with diethyl ether (3×200 mL). The combined ether layers were dried over MgSO4, filtered, then concentrated under reduced pressure to afford 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (4.27 g, 37% from 3,3,3-trifluoro-2,2-dimethylpropionic acid) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.77 (s, 2H), 1.43 (s, 6H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[N:10]([O-])=O.[Na+].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[N:5]=[N:10][C:15]1[NH:14][CH:18]=[CH:17][N:16]=1
Reactant: c1c[nH]cn1
Reactant: Nc1ccccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Clc1ccccc1N=Nc1ncc[nH]1
Temperature: 0 °C
Yield: 103.3 %

Procedure:
To a mixture of 750 cubic centimeters (cc) of ice water and 250 cc of concentrated hydrochloric acid which was stirred and cooled to ~0° C was added 128.0 grams (1.0 mole) of 2-chloroaniline. Immediately a white solid formed. This mixture was stirred at ~0° C as 69.0 grams (1.0 mole) of sodium nitrite was added over a period of ~15 minutes. After the completion of the addition, the newly formed solution was stirred for ~15 minutes and 68.0 grams (1.0 mole) of imidazole was added. After a short period, 5.0 liters of water was added and the temperature was brought to ~0° C. To this mixture was slowly added with vigorous stirring 160.0 grams of anhydrous sodium carbonate and the mixture thereafter stirred at ~0° C for 3.0 hours. At the end of the period, the solution was filtered and the solid which was recovered was washed with water. The solids were thereafter mixed with dilute hydrochloric acid (200 cc of concentrated hydrochloric acid diluted to 2.0 liters) and stirred at room temperature for ~1.0 hour. The insolubles were removed by filtration and discarded. The filtrate was made basic with 140.0 grams of sodium carbonate and the crystals which formed were removed by filtration, washed with water and dried to give 213.5 grams of crude 2-((2-chlorophenyl)azo)imidazole melting at 173°-177° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:30](=O)[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:28])[CH3:27])[CH2:10][CH2:9]1.Cl.[CH3:34][O:35][NH2:36].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:34][O:35][N:36]=[C:30]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:29])[C:15]3[CH:20]=[C:19]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:18]=[CH:17][C:16]=3[O:25][CH:26]([CH3:28])[CH3:27])[CH2:12][CH2:13]2)=[C:2]([F:1])[CH:3]=1)[CH3:31]
Reactant: CON
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON=C(C)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.12 mmol of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone was dissolved in 1 ml of a 1:1 mixture of ethanol and water. 0.8 mmol of O-methyl-hydroxylamine hydrochloride was added, followed by 8.4 mmol of sodium acetate. The slurry was stirred overnight at room temperature, diluted with water, extracted with ethyl acetate, dried and concentrated. The resulting gum was triturated with diethyl ether/heptane to yield the title compound as a colorless solid. MS (m/e): 492.3 (MH+, 100%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)N4CCOCC4)c3)C(C)(C)C2=O)cc1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 150 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 3 mL of dioxane and 36.9 mg of morpholine. After chromatography on a column of silica, eluting with a mixture of heptane/ethyl acetate (gradient from 100/0 to 0/100 by volume), 74 mg of N-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]methyl}pyridin-2-yl)morpholine-4-carboxamide are obtained in the form of a yellow wax, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[C:24]([CH3:31])=[CH:23][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O-:16])=[O:15])=[C:10]([S:17]([F:22])([F:21])([F:20])([F:19])[F:18])[CH:9]=1)(=[O:4])=[O:3].[Na+].[CH3:33]N([CH:36]=[O:37])C>>[CH3:1][S:2]([C:5]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:33])(=[O:16])=[O:15])=[C:10]([S:17]([F:19])([F:18])([F:20])([F:21])[F:22])[CH:9]=2)=[CH:23][C:24]([CH3:31])=[C:25]([CH:26]=1)[C:27]([O:29][CH3:30])=[O:28])(=[O:3])=[O:4].[CH3:1][S:2]([C:5]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([O:37][CH3:36])=[O:15])=[C:10]([S:17]([F:20])([F:22])([F:21])([F:18])[F:19])[CH:9]=2)=[CH:23][C:24]([CH3:31])=[C:25]([CH:26]=1)[C:27]([O:29][CH3:30])=[O:28])(=[O:3])=[O:4]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc(S(=O)[O-])c(S(F)(F)(F)(F)F)c2)cc1C
Reactant: CN(C)C=O
Agent: [Na+]
Product: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc(S(=O)OC)c(S(F)(F)(F)(F)F)c2)cc1C
Product: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc(S(C)(=O)=O)c(S(F)(F)(F)(F)F)c2)cc1C
Temperature: 45 °C
Reaction time: 9 h

Procedure:
3.0 g of sodium 4-(2-methanesulfonyl-4-methoxycarbonyl-5-methyl-phenoxy)-2-pentafluorosulfanylbenzenesulfinate (example 4) were dissolved in 100 ml of anhydrous DMF, 4.0 g of CH31 were added and the mixture was stirred at 45° C. for 9 h. The reaction mixture was subsequently left to stand at RT for 2 days. The solvent was then removed under reduced pressure and the residue taken up with 100 ml of water and 100 ml of EA. 50 ml of a 5% aqueous NaHSO4 solution were then added and the phases were separated. Subsequently, the mixture was extracted 3 times with 100 ml each time of EA. The mixture was dried over MgSO4, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel with 1:1 MTB/DIP. 0.59 g of methyl 5-methanesulfonyl-4-(4-methanesulfonyl-3-pentafluorosulfanylphenoxy)-2-methylbenzoate and 0.49 g of methyl 5-methanesulfonyl-4-(4-methoxysulfinyl-3-pentafluorosulfanylphenoxy)-2-methylbenzoate were obtained.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]2[OH:19])(=O)=O)=CC=1.O[C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[OH:19][C@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]1[CH2:12][O:11][C:25]1[CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][N:30]2[C:31](=[O:40])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]2=[O:39])[CH:22]=[CH:21][CH:26]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCC[C@@H]2O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OC[C@H]2CCCC[C@@H]2O)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of ((1R,2S)-2-hydroxycyclohexyl)methyl 4-methylbenzenesulfonate (0.334 g, 1.24 mmol), compound 58 (0.432 g, 1.54 mmol), cesium carbonate (0.562 g, 1.73 mmol) in anhydrous DMF (8 mL) was stirred at 60° C. under argon for 18 hrs, and then concentrated under reduced pressure. Water was added and the product was extracted with EtOAc three times. Combined fractions were washed with sat. NH4Cl, brine, and concentrated under reduced pressure. The residue was purified by flash chromatography (20% to 70% EtOAc/hexanes gradient) to afford 2-(3-(3-(((1R,2S)-2-hydroxycyclohexyl)methoxy)phenyl)propyl)isoindoline-1,3-dione as a colorless oil. Yield (0.191 g, 41%). 1H NMR (400 MHz, DMSO-d6) δ 7.76-7.85 (m, 4H), 7.09 (t, 7.6 Hz, 1H), 6.69-6.74 (m, 2H), 6.61-6.65 (m, 1H), 4.34 (d, J=4.1 Hz, 1H), 3.91 (dd, J=7.0, 9.2 Hz, 1H), 3.86-3.89 (m, 1H), 3.67 (dd, J=6.9, 9.2 Hz, 1H), 3.53-3.60 (m, 2H), 2.50 (t, J=7.6 Hz, 2H), 1.80-1.91 (m, 2H), 1.73-1.80 (m, 1H), 1.51-1.66 (m, 3H), 1.28-1.44 (m, 4H), 1.17-1.25 (m, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH2:7].[N+:8]([C:11]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:12]=1[O:13][CH:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])([O-:10])=[O:9]>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:15](=[O:16])[CH:14]([O:13][C:12]1[CH:20]=[C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])[CH:22]=[CH:23][C:11]=1[N+:8]([O-:10])=[O:9])[CH2:18][CH3:19]
Reactant: CCC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: NCC1OCCO1
Solvent: ClCCl
Product: CCC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)NCC1OCCO1
Temperature: -15 °C

Procedure:
N-(1,3-Dioxolan-2-ylmethyl)amine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]butanoyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. The residue is then recrystallized from a toluene/hexane mixture to yield the desired product N-(1,3-dioxolan-2-ylmethyl)-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]butyramide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[C:24]([C:25]4[CH:26]=[C:27]([C:33]5[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][C:34]=5[CH3:46])[CH:28]=[N:29][C:30]=4[O:31][CH3:32])=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)[C@H:13]2[CH3:51])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[F:53][CH:54]1[CH2:57][NH:56][CH2:55]1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[F:53][CH:54]1[CH2:57][N:56]([C:21]2[N:20]=[C:19]([CH2:18][N:14]3[C@@H:13]([CH3:51])[C@@H:12]([C:4]4[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]([F:1])[CH:3]=4)[O:16][C:15]3=[O:17])[C:24]([C:25]3[CH:26]=[C:27]([C:33]4[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[CH:35][C:34]=4[CH3:46])[CH:28]=[N:29][C:30]=3[O:31][CH3:32])=[CH:23][N:22]=2)[CH2:55]1
Reactant: FC1CNC1
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-{5-[4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (INTERMEDIATE 48, 96 mg, 0.131 mmol) in THF (1.5 mL) was added 3-fluoroazetidine hydrochloride (44 mg, 0.394 mmol) and triethylamine (0.082 mL, 0.591 mmol). The resulting mixture was subjected to microwave irradiation at 120° C. for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (sodium sulfate), filtered and concentrated to give crude tert-butyl 4-{5-[2-(3-fluoroazetidin-1-yl)-4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (95 mg, 0.131 mmol). LCMS (M+H)+: 726.2.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=2)=[N:11][N:12]=1.[CH3:32][NH2:33]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:33][CH3:32])=[CH:15][CH:14]=2)=[N:11][N:12]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)cc1
Reactant: CN
Product: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(C(=O)N(C)C)cc4)cnc3N)o2)cc1
Temperature: 100 °C
Yield: 19 %

Procedure:
4-[5-amino-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (70 mg, 0.1460 mmol) was treated with methylamine (2 mL of 33% w/w solution in ethanol), and the resulting mixture stirred heated at 100° C. for 10 min. The reaction mixture was cooled to room temperature and filtered. The filtrate was collected and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions were passed througha carbonate cartridge leuting with MeOH/CH2Cl2. The eluent was concentrated in vacuo and the solid triturated with acetonitrile to give the product as a yellow solid (11.4 mg, 19% yield); 1H NMR (400 MHz, DMSO) d 2.30 (s, 3H), 2.98-3.02 (m, 6H), 3.77 (s, 2H), 7.55 (d, 2H), 7.61 (d, 2H), 7.78 (br s, 2H), 8.11 (d, 2H), 8.17 (d, 2H) and 8.98 (s, 1H) ppm; MS (ES+) 430.31
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6](Br)[N:7]=1.[O:10]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:26]([O-:29])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[O:10]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([O:29][C:26]4[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=4)=[CH:13][CH:12]=3)[N:7]=2)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ncc(Br)nc1Br
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Nc1ncc(-c2ccc(Oc3ccccc3)cc2)nc1-c1ccc(Oc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
A solution of 1.00 equivalents (eq.) of 3,5-dibromo-2-aminopyrazine (2) in 3 mL toluene is treated with 10 mole percent tetrakis(triphenylphospine) palladium under nitrogen at room temperature. To this solution is added directly 2.00 eq. of 4-phenoxyphenyl boronic acid at room temperature and then 2 mL Na2CO3 (1.0 M) solution. The reaction vial is capped and the reaction stirred under nitrogen at 90° C. for 10 hours. The toluene layer is separated and removed under reduced pressure, and the resulting oil is purified via flash chromatography to provide (3). MF=C28H21N3O2, MW=431.49 Mass Spec m/z (M++1) 432.14.
Reaction SMILES: [CH3:1][C:2]1[C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:19].[CH:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH2:21].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH2:23]([O:22][C:20]([C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:19])[O:5][CH2:4]2)=[CH2:21])[CH2:24][CH2:25][CH3:26]
Reactant: C=COCCCC
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)ccc2c1COC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(OCCCC)c1ccc2c(c1C)COC2=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a 1 L 3-neck was charged trifluoromethanesulfonic acid 4-methyl-1-oxo-1,3-dihydro-isobenzofuran-5-yl ester (63.0 g, 213 mmol), DMF (315 mL), butyl vinyl ether (138 mL, 1063 mmol) then Et3N (35.6 mL, 255 mmol). The solution was sparged with N2 for 20 min. To the solution was added Pd(OAc)2 (1.19 g., 5.32 mmol) and DPPP (2.41 g., 5.85 mmol) and sparged for an additional 10 min then heated to 80° C. After a 1 hr age, the solution was cooled to <10° C. then quenched with 630 mL EtOAc and washed with 5% NH4Cl (2×315 mL), 10% brine (2×315 mL), dried over MgSO4, filtered, concentrated by rotary evaporation and flushed with EtOAc (3×100 mL) to remove excess butyl vinyl ether, providing crude 5-(1-butoxy-vinyl)-4-methyl-3H-isobenzofuran-1-one.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][CH:5]=1.Cl.[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([CH3:28])=[CH:21][CH:20]=2)[CH2:23][CH2:24]1
Reactant: Cc1ccc(C2CCNCC2)cc1
Reactant: COc1ccc2[nH]cc(CCBr)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCN3CCC(c4ccc(C)cc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 80 h

Procedure:
A solution of 8.8 g of 3-(2-bromoethyl)-5-methoxy indole in 100 ml of dimethylformamide is added to a stirring mixture of 4-(4-toluyl)piperidine hydrochloride [Example 5(a)]and 10.1 g of potassium carbonate in 400 ml of dimethylformamide and the reaction mixture is stirred at ambient temperature for 80 hours and then at 50° C. for 10 additional hours. It is cooled to ambient temperature, filtered, and 2 liters of water are added dropwise to produce a precipitate. The precipitate is triturated with ether and eluted with a 5% methanol in benzene solution through a silica gel column. The precipitate is recrystallized from an ethanol-water mixture to give off-white crystals, mp 131°-133° C., 5-methoxy-3-{2-[4-(4-toluyl)piperdyl]ethyl}indole.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:15][C@@H:16]1[CH2:24][C@@H:19]2[O:20][C:21](=[O:23])[CH2:22][C@@H:18]2[C@H:17]1[CH2:25][OH:26])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.C1(C)C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[C:7]([O:15][C@@H:16]1[CH2:24][C@@H:19]2[O:20][C:21](=[O:23])[CH2:22][C@@H:18]2[C@H:17]1[CH:25]=[O:26])(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of anhydrous chromium trioxide (20.8 g, 208 mmol) in methylene chloride (400 mL) was stirred and cooled in an ice bath as anhydrous pyridine (32.7 mL, 406 mmol) was added. After 15 min at 0° C., the mixture was allowed to warm to ambient temperature for 2 h. The reaction mixture was cooled to 0° C. and treated with a pre-cooled solution of (3aR,4S,5R,6aS)-5-(benzoyloxy)hexahydro-4-(hydroxymethyl)-2H-cyclopenta[b]furan-2-one (Corey lactone, 9.4 g, 34 mmol) in methylene chloride (400 mL) After 5 min, the reaction was diluted with toluene (240 mL) and filtered. The solid was washed with toluene. The combined filtrate was concentrated to give (3aR,4R,5R,6aS)-5-(benzoyloxy)hexahydro-2-oxo-2H-cyclopenta[b]furan-4-carboxaldehyde. Toluene was added to give about 300 mL of solution.