Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[N:21]#[C:22][NH2:23].OS(C(F)(F)F)(=O)=O>C1COCC1>[C:22](=[NH:21])([O:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[CH:7]=[N:8][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:4][CH:5]=2)=[CH:11][CH:12]=1)[NH2:23]
Reactant: OCCc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Reactant: N#CN
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Temperature: 55 °C
Yield: 57 %

Procedure:
To a solution of 2-(4-{[6-(trifluoromethyl)-3-pyridinyl]oxy}phenyl)ethanol (1.95 g, 6.88 mmol) and cyanamide (0.5 g, 11.89 mmol) in dry THF (20 mL) under nitrogen was added triflic acid (1 mL, 11.26 mmol). The mixture was heated at 55° C. for 4 h. Purification via reverse phase flash chromatography afforded the title compound (1.72 g, 3.92 mmol, 57.0% yield) as a white solid. LCMS: rt=2.42 min, [M+H+]=326
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[CH2:2]1.Cl.O1CCOCC1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:41][CH:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]2[N:54]=[C:53]([C:55]3[C:59]([CH2:60][CH2:61][CH3:62])=[C:58]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[O:57][N:56]=3)[O:52][N:51]=2)=[CH:46][CH:45]=1)[OH:43]>>[OH:43][CH:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]2[N:54]=[C:53]([C:55]3[C:59]([CH2:60][CH2:61][CH3:62])=[C:58]([C:63]4[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=4)[O:57][N:56]=3)[O:52][N:51]=2)=[CH:46][CH:45]=1)[CH2:41][N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][C:8]([OH:10])=[O:9])[CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@H]1CCCNC1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCC[C@H](CC(=O)O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
(R)-tert-Butyl 2-(piperidin-3-yl)acetate (66 mg, 0.331 mmol) was treated with 4N HCl/dioxane for 30 minutes. The reaction mixture was concentrated in vacuo and dried. The solid material was dissolved in DMSO (2 mL) and tetrabutylammonium hydroxide (0.352 mL, 0.352 mmol) was added. After stirring 15 minutes, 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (40 mg, 0.088 mmol) was added. The reaction mixture was heated at 80° C. for 2 hours, and then filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 20 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 9 mg of 2-((3R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.11 (2H, m), 7.68-7.75 (2H, m), 7.59 (2H, m, J=8.35 Hz), 7.43-7.55 (3H, m), 5.16 (1H, dd, J=9.01, 4.61 Hz), 3.71-3.89 (1H, m), 3.50-3.67 (2H, m), 3.24 (1H, d, J=2.42 Hz), 2.96 (2H, dd, J=8.90, 6.92 Hz), 2.83-2.93 (1H, m), 2.72 (1H, td, J=11.86, 5.27 Hz), 2.16-2.39 (3H, m), 1.77-2.00 (3H, m), 1.59-1.75 (2H, m, J=7.61, 7.61, 7.61, 7.61, 7.36 Hz), 1.13-1.32 (1H, m), 0.95 (3H, t, J=7.25 Hz). MS (m+1)=517. HPLC Peak RT=3.32 minutes (Analytical Method A). Purity=95%.
Reaction SMILES: [CH2:1]([S:5]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]([O:20]C)=O)[CH:12]=[CH:11][C:10]=2[CH2:9]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[K].[NH2:23][OH:24].C(O)(=O)C>CO>[CH2:1]([S:5]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]([NH:23][OH:24])=[O:20])[CH:12]=[CH:11][C:10]=2[CH2:9]1)(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)N1CCc2nc(C(=O)OC)ccc2C1
Reactant: NO
Agent: [K]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCS(=O)(=O)N1CCc2nc(C(=O)NO)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
To a microwave vial containing methyl 6-(butylsulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate was added MeOH (1 mL) and hydroxylamine potassium salt (1 mL, 1.76 mmol, 1.76 M in MeOH). The solution was shaken at rt for 1 h, then acetic acid (0.102 mL, 1.8 mmol) was added to quench excess base. The solvent was then concentrated. To the resulting residue was added DMSO (1.2 mL) and after filtration, the solution underwent purification via prep-HPLC to give 6-(butylsulfonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide (13.3 mg, 28.3%). LC-MS: (FA) ES+ 314; 1H NMR (Methanol-d4, 300 MHz) δ 7.97 (d, J=8.1 Hz, 1 H), 7.76 (d, J=7.9 Hz, 1 H), 4.59 (s, 2 H), 3.70 (t, J=6.0 Hz, 2 H), 3.13 (m, 4 H), 1.77 (m, 2 H), 1.47 (m, 2 H), 0.95 (t, J=7.3 Hz, 3 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])=[C:20]([CH2:22][OH:23])[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(C(C)C)CC)(C)C.[I-].[Na+].[F:52][C:53]([F:57])([F:56])[CH2:54][O-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[O:18][C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])=[C:20]([CH2:22][O:23][CH2:54][C:53]([F:57])([F:56])[F:52])[N:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(CO)c(-c3ccc(F)cc3F)o2)CC1
Reactant: [O-]CC(F)(F)F
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(c2nc(COCC(F)(F)F)c(-c3ccc(F)cc3F)o2)CC1
Temperature: 0 °C

Procedure:
To a three neck 0.5 liter round bottom flask fitted with mechanical stirrer, nitrogen inlet and dropping funnel is added 4-[5-(2,4-Difluoro-phenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidine-1-carboxylic acid benzyl ester, methane sulfonic anhydride (5.87 g, 33.7 mmol), and 150 mL of dry tetrahydrofuran. The mixture is stirred and cooled to 0° C., followed by dropwise addition of diisopropyl ethylamine (8.4 mL, 48 mmol). The mixture is stirred for 1 hour at 0° C. and then allowed to warm to room temperature. To the resultant mixture is then added sodium iodide (7.75 g, 51.7 mmol), and the mixture is stirred for an additional three hours. The sodium 2,2,2-trifluoroethoxide (0.151 mmol in 80 mL of dry tetrahydrofuran) is added dropwise over a 15 minute period and the resulting mixture is stirred for an additional 1 hour. The mixture is cooled to 0° C. and carefully quenched with 125 mL of water. After the addition was complete, the mixture is extracted with water and methylene chloride. The aqueous is washed with an additional three portions of methylene chloride, using 300 mL volumes. The organics are combined, washed with brine, dried over magnesium sulfate and concentrated to a thick residue. The residue is purified by preparative medium performance liquid chromatography to give upon concentration the desired fractions of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1C(OCC)=O.Cl>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:18])[CH:3]=1
Reactant: CCOC(=O)C1=C(O)c2ccccc2[C@@](C)(CCC(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CC[C@@]1(C)C(=O)C=C(O)c2ccccc21
Temperature: 25 °C
Yield: 87.7 %

Procedure:
A solution of Example 39D (3.10 g, 9.80 mmol) in 1,4-dioxane (25 mL) was treated with aqueous 1N hydrochloric acid solution (25 mL) and refluxed for 3 hours. The mixture was cooled to 25° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated in hot hexane and filtered. The precipitate was dried to give the title compound (2.10 g, 88%). 1H NMR (300 MHz, CDCl3): δ ppm 0.44 (m, 0.5 H) 0.73 (m, 3.5 H) 0.80 (m, 3 H) 1.06 (m, 1 H) 1.39 (m, 1 H) 1.56 (s, 1.5 H) 1.59 (s, 1.5 H) 2.04 (m, 1 H) 2.30 (m, 1 H) 3.74 (s, 0.5 H) 3.75 (s, 0.5 H) 6.63 (s, 0.5 H) 7.46 (m, 2 H) 7.66 (m, 1H) 8.08 (m, 0.5 H) 8.20 (m, 0.5 H).
Reaction SMILES: CC1(C)[O:10][C:9]2[CH:8]=[CH:7][C:6]([C@H:11]3[O:15]C(C4C=CC=CC=4)=[N:13][C@@H:12]3[C:22]([O:24]C)=[O:23])=[CH:5][C:4]=2[O:3]1>Cl>[CH:7]1[C:6]([C@@H:11]([OH:15])[C@H:12]([NH2:13])[C:22]([OH:24])=[O:23])=[CH:5][C:4]([OH:3])=[C:9]([OH:10])[CH:8]=1
Reactant: COC(=O)[C@H]1N=C(c2ccccc2)O[C@@H]1c1ccc2c(c1)OC(C)(C)O2
Agent: Cl
Product: N[C@H](C(=O)O)[C@H](O)c1ccc(O)c(O)c1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
Methyl (4S, 5R)-5-[3, 4-(dimethyl methylenedioxy)phenyl]-2-phenyl-2-oxazoline-4-carboxylate (500 mg, 1.41 mmol) was added to 2N-hydrochloric acid (10 ml) with stirring at room temperature, and the mixture was then refluxed for 16 hours. After cooling to room temperature, about 25° C., the reaction mixture was concentrated under reduced pressure and neutralized with an aqueous 1N-sodium hydroxide solution to obtain a precipitated crystal. The precipitated crystal then was filtered to obtain 265 mg (1.24 mmol, yield: 88%) of L-threo DOPS.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[C:21]=1[N:28]1[C:32]2=[N:33][CH:34]=[N:35][C:36]([O:37][C@@H:38]([CH2:49][O:50][C@H:51]([CH3:64])[CH2:52][O:53][Si](C(C)C)(C(C)C)C(C)C)[C:39]([NH:41][C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][N:43]=3)=[O:40])=[C:31]2[CH:30]=[N:29]1>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[C:21]=1[N:28]1[C:32]2=[N:33][CH:34]=[N:35][C:36]([O:37][C@@H:38]([CH2:49][O:50][C@H:51]([CH3:64])[CH2:52][OH:53])[C:39]([NH:41][C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][N:43]=3)=[O:40])=[C:31]2[CH:30]=[N:29]1
Reactant: Cc1ccc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](CO[C@H](C)CO)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
1M tetrabutylammonium fluoride in THF (0.503 mL, 0.50 mmol) was added to (2S)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AH8) (334 mg, 0.50 mmol) in THF (10 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (2 mL), diluted with DCM (25 mL) and poured onto a phase separator. The organic phase was reduced and the residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents to afford the product (129 mg, 50.5%). 1H NMR (400 MHz, CDCl3) d 1.21-1.14 (3H, m), 2.30 (3H, s), 3.62 (2H, m), 3.78 (1H, m), 4.14-4.03 (1H, m), 4.28 (1H, dd), 6.10-6.03 (1H, m), 7.54 (1H, dd), 7.62 (1H, t), 7.79 (1H, m), 7.86 (1H, m), 8.07 (2H, d), 8.51 (1H, d), 8.62 (1H, d), 9.28-9.18 (1H, m), OH not observed. m/z (ES+) (M+H)+=508; HPLC tR=1.92 min. ee 90%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:10])[C:7]=1[O:8][CH3:9].Br[C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=2[C:23]2[CH:24]=[CH:25][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH:5]=[C:6]([Cl:10])[C:7]=1[O:8][CH3:9]
Reactant: NS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Reactant: COc1c(Cl)cc(B(O)O)cc1Cl
Product: COc1c(Cl)cc(-c2cc(F)c(F)cc2-c2ccc(S(N)(=O)=O)cc2)cc1Cl

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 3,5-dichloro-4-methoxyphenylboronic acid (Step 2) was reacted with 4-(2-bromo-4,5-difluorophenyl]benzenesulfonamide (Step 3) to give 4-[2-(3,5-dichloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide as a colorless solid: mp 145.5-146.0° C.; NMR (CDCl3) δ 3.89 (s, 3H), 4.78 (s, 2H), 6.98 (s, 2H), 7.18-7.29 (m, 4H), 7.85 (d, J=8 Hz, 2H); MS (FAB) m/z 450 (M+Li)+; HRMS calc'd for (M+H)+ 444.0039, found 444.0052. Anal. Calc'd for C19H13NCl2F2O3S: C, 51.37; H, 2.95; N, 3.15. Found: C, 51.59; H, 3.03; N, 3.15.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:28]=[CH:27][C:11]2[S:12][C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:14]([CH2:15][C:16](OCC)=[O:17])[C:10]=2[CH:9]=1>C(OCC)C>[Cl:7][C:8]1[CH:28]=[CH:27][C:11]2[S:12][C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:14]([CH2:15][CH2:16][OH:17])[C:10]=2[CH:9]=1
Reactant: CCOC(=O)Cc1c(-c2ccccc2)sc2ccc(Cl)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 11.5 parts by weight of lithium aluminum hydride in 100 parts by volume of refluxing ethyl ether under a nitrogen atmosphere is added over a 0.25 hour addition period 25.0 parts by weight of ethyl 5-chloro-2-phenylbenzo[b]thiophene-3-acetate in 100 parts by volume of ethyl ether. The resulting mixture is heated at reflux temperature for 48 hours before cooling to 0° C. and quenching with cautious sequential addition of 11.5 parts by volume of water, 11.5 parts by volume of 15% aqueous sodium hydroxide solution and 34.5 parts by volume of water. The reaction mixture is stirred for an additional two hours at 0° C. before the granular aluminum salts are removed by vacuum filtration. The aluminum salts are then washed with a liberal amount of ethyl ether. Concentration of the filtrate in vacuo affords 5-chloro-2-phenylbenzo[b]thiophene-3-ethanol as an off-white solid material. This material is represented by the following structural formula ##STR14##
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>O1CCOCC1>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:21][CH2:20]1
Reactant: ClC(c1ccccc1)c1cc2ccccc2o1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: CN1CCN(C(c2ccccc2)c2cc3ccccc3o2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
25.4 g of α(benzofuran-2-yl)benzyl chloride dissolved in 150 ml of dioxane are added slowly at about 60°-70° C. to 26 g of 1-methyl-piperazine in 150 ml of dioxane. After the addition, the mixture is stirred at about 70° C. for a further two hours. The solvent is removed under reduced pressure, the residue is then dissolved in 5% sodium bicarbonate and extracted with ethyl ether. After washing the ether phase with water and drying with sodium sulphate, the hydrochloride is precipitated by bubbling in anhydrous hydrochloric acid gas: M.P. 186°-188° C. (isopropanol).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][O:4][CH2:3]1.[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[OH-].[Na+]>O>[S:12]([C:9]1[CH:10]=[CH:11][C:6]([CH3:16])=[CH:7][CH:8]=1)([O:1][C:2]1[CH2:3][O:4][CH:5]=1)(=[O:14])=[O:13]
Reactant: OC1COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2=COC2)cc1
Reaction time: 1 h
Yield: 94 %

Procedure:
To a stirred suspension of 315 g of 3-hydroxyoxetane (3.4 Moles) and 743 g (3.9 moles) of technical grade p-toluenesulfonyl chloride in 600 mL of water, was added dropwise, over a period of 25 minutes a solution of 218 g (5.45 moles) of sodium hydroxide in 225 mL of water. The reaction was exothermic and ice bath cooling was used to keep the reaction temperature below 70° C. When the exothermic reaction subsided (10 minutes), the cooling bath was removed and the reaction temperatures was allowed to decrease to 40° C. over a 1 hour period. The product was isolated by filtration, washed with four 200 ml portions of warm (45°-55° C.) water, and air dried to give 730 g (94% yield) of 3-oxetyl tosylate, mp 86°-88° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([CH3:20])=[CH:15][N:14]=1.CO>O>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](=[O:10])[NH:7][C:6]=3[CH:11]=2)[C:16]([CH3:20])=[CH:15][N:14]=1
Reactant: Nc1ccc2oc(=O)[nH]c2c1
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: O
Solvent: CO
Product: Cc1cnc(Cl)nc1Nc1ccc2oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 71 %

Procedure:
To a vial with 5-aminobenzo[d]oxazol-2(3H)-one (300.1 mg, 2.0 mmol) and 2,4-dichloro-5-methylpyrimidine (423.8 mg, 2.6 mmol), MeOH (8 mL) and H2O (2 mL) were added. The turbid mixture was stirred at room temperature for 64 h. Precipitate from reaction mixture was collected by filtration, washing with EtOAc (3 mL×2), and was further dried in vacuo. 5-(2-Chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one was obtained as an off-white solid: 394 mg (71% yield); 1H NMR (300 MHz, DMSO) δ 11.68 (br s, 1H), 8.62 (s, 1H), 7.94 (d, J=0.8, 1H), 6.97 (d, J=2.0, 1H), 6.82 (d, J=8.1, 1H), 6.74 (dd, J=2.0, 8.1, 1H), 2.15 (s, 3H); LCMS (M+) m/z 277.10.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([N:20]2[C:24]([CH3:25])=[C:23](I)[C:22]([CH3:27])=[N:21]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>[Pd].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.CCO.O>[CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([N:20]2[C:24]([CH3:25])=[C:23]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)[C:22]([CH3:27])=[N:21]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)n2nc(C)c(I)c2C)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)n2nc(C)c(-c3ccc(F)cc3)c2C)cc1
Temperature: -78 °C
Yield: 87.9 %

Procedure:
To a stirring solution of N,N-Diethyl-4-[(4-iodo-3,5-dimethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-methyl]-benzamide (145 mg, 0.281 mmol) in 20 Ml EtOH/H2O (9:1) at room temperature was added 4-fluorobenzene boronic acid (118 mg, 0.842 mmol), Na2CO3 (90.0 mg, 0.842 mmol) and tetrakis(triphenylphosphine) palladium (0) (30.0 mg, 0.005 mmol). The mixture was cooled to −78° C., de-oxygenated under reduced pressure and purged with nitrogen gas. The mixture was refluxed for 2 hours, cooled to room temperature, filtered through a Celite pad and concentrated under reduce pressure. Purification of the crude material was accomplished by flash chromatography on a 2×15 cm column, eluting with 30% ethyl acetate/hexanes, collecting 8 Ml fractions. The product containing fractions were collected and concentrated to give the desired product (120 mg, 88%) as a clear colorless solid. 300 MHz 1H NMR (CDCl3) δ 7.33 (d, J=8.3 Hz, 2H), 7.16-7.23 (m, 5H), 7.04-7.15 (m, 2H), 6.71-6.84 (m, 3H), 6.55 (s, 1H), 3.74 (s, 3H), 3.52 (br s, 2H), 3.27 (br s, 2H), 2.19 (s, 3H), 2.16 (s, 3H), 1.21 (br s, 3H), 1.09 (br s, 3H), MS (M+1) 486.2.
Reaction SMILES: [C:1]([C:5]1[CH:52]=[CH:51][C:8]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]3[CH:24]=[C:23]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH:22]=[CH:21][C:20]=3[NH:31][C:32]([C:34]3[CH:35]=[C:36]([CH:48]=[CH:49][CH:50]=3)[CH2:37][S:38][CH2:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])=[O:33])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]3[CH:24]=[C:23]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH:22]=[CH:21][C:20]=3[NH:31][C:32]([C:34]3[CH:35]=[C:36]([CH:48]=[CH:49][CH:50]=3)[CH2:37][S:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:33])[CH:14]=2)=[O:12])=[CH:51][CH:52]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(C(C)(C)C)cc3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(CNC(=O)c2ccnc(-c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((4-tert-butylbenzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)propanoate (100 mg, 0.14 mmol, 1.00 equiv) in dichloromethane (2 mL), and trifluoroacetic acid (160 mg, 1.40 mmol, 10.00 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (95 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 50 mg (46%) of a white solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 9.03-9.05 (d, J=5.4 Hz, 1H), 8.80-8.83 (d, J=9.3 Hz, 1H), 8.42 (s, 1H), 8.16-8.17 (d, J=2.7 Hz, 1H), 8.00 (s, 1H), 7.90-7.90 (d, J=1.5 Hz, 1H), 7.87-7.89 (m, 2H), 7.71-7.75 (dd, J=9.02 Hz, J′=2.7 Hz, 1H), 7.60-7.62 (m, 1H), 7.50-7.55 (m, 1H), 7.40-7.42 (m, 2H), 7.31-7.39 (m, 2H), 4.61 (s, 2H), 3.91 (s, 2H), 3.70-3.73 (m, 4H), 2.70 (m, 2H), 2.56-2.51 (m, 2H), 2.06-2.09 (m, 4H), 1.84-1.86 (m, 1H), 1.32-1.33 (m, 9H). MS (ES, m/z): 665 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([NH:28][C@H:29]([B:46]2[O:54]C3C(C)(C4CC(C3)C4(C)C)[O:47]2)[CH2:30][C:31]2[C:32](OC)=[C:33]([CH:41]=[CH:42][CH:43]=2)[C:34]([O:36]C(C)(C)C)=[O:35])=[O:27])[CH:13]=[CH:14][C:15]=1[CH2:16][NH:17]C(OC(C)(C)C)=O)=O)(C)(C)C.B(Cl)(Cl)Cl>>[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([NH:28][C@H:29]2[CH2:30][C:31]3[CH:43]=[CH:42][CH:41]=[C:33]([C:34]([OH:36])=[O:35])[C:32]=3[O:54][B:46]2[OH:47])=[O:27])[CH:13]=[CH:14][C:15]=1[CH2:16][NH2:17]
Reactant: COc1c(C[C@H](NC(=O)Cc2ccc(CNC(=O)OC(C)(C)C)c(CNC(=O)OC(C)(C)C)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: NCc1ccc(CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)cc1CN

Procedure:
Prepared from tert-butyl 3-((2R)-2-(2-(3,4-bis((tert-butoxycarbonylamino)methyl)phenyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate and BCl3 following the procedure described in Step 2 of Example 3. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[CH:34]=[CH:33][O:32][CH:31]=2)=[O:29])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1>>[O:32]1[CH:33]=[CH:34][C:30]([C:28]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[C:26]([C:2]3[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:25]=2)=[O:29])=[CH:31]1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(NC(=O)c4ccoc4)ccc3C)nc2)c1

Procedure:
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(3-methoxybenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 3.17 min, MH+442. NMR: δH [2H6]-DMSO 9.99, (1H, s), 9.29, (1H, t), 9.15, (1H, d), 8.38, (1H, s), 8.34, (1H, dd), 7.81, (2H, m), 7.75, (1H, d), 7.67, (1H, d), 7.31-7.25 (2H, m), 7.00, (1H, s), 6.94, (2H, m), 6.84, (1H, d), 4.51, (2H, d), 3.75, (3H, s), 2.32, (3H, s).