Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15](=[O:31])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[C:17]=3[F:30])[CH:12]=2)[NH:7][CH:6]=1)=[O:4].[CH3:32][NH:33][CH3:34].CO>CCO>[CH3:32][N:33]([CH3:34])[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15](=[O:31])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[C:17]=3[F:30])[CH:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: CNC
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CCl)c3c2)c1F
Solvent: CO
Solvent: CCO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CN(C)C)c3c2)c1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 40.4 %

Procedure:
N-(3-(2-Chloroacetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.181 mL, 0.0361 mmol), EtOH (0.2 mL), and dimethylamine as a solution in MeOH (0.181 mL, 0.361 mmol) was charged to a 2 dram vial. The vial was capped and stirred at 60° C. for 4 hours. The mixture was concentrated under reduced pressure. The residue was taken up in 1M HCL (1 mL) and washed with EtOAc (2×1 mL). The aqueous portion was neutralized and extracted with 25% isopropyl alcohol (“IPA”)-DCM (3×2 mL), which was concentrated to provide N-(3-(2-(dimethylamino)acetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (7 mg, 40.4%) as a solid. 1H NMR (400 MHz, CD3OD) δ 9.03-9.06 (m, 1H), 8.56-8.58 (m, 1H), 8.46 (s, 1H), 7.63-7.69 (m, 1H), 7.12-7.16 (m, 1H), 3.11-3.14 (m, 2H), 3.03 (s, 6H), 2.90 (s, 2H), 1.85-1.90 (m, 2H), 1.05-1.08 (m, 3H); m/z (APCI-pos) M+1=480.1.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH:7]1[CH2:21][CH2:20][C:10]2([CH2:14][NH:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11]2)[CH2:9][CH2:8]1)([CH3:4])[CH3:3].C(N(CC)CC)C.[CH:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39](Cl)=[O:40])=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH:7]1[CH2:21][CH2:20][C:10]2([CH2:14][N:13]([C:39]([O:38][CH2:37][C:34]3[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=3)=[O:40])[CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11]2)[CH2:9][CH2:8]1)([CH3:3])[CH3:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CC2(CCC(O[Si](C)(C)C(C)(C)C)CC2)CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC2(CCC(O[Si](C)(C)C(C)(C)C)CC2)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a solution of ethyl 8-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-azaspiro[4.5]decane-3-carboxylate (110) (10.61 g, 31.3 mmol) dissolved in dry DCM, triethylamine was added (10.8 mL, 78 mmol), cooled to 0° C. followed by the addition of Cbz-Cl (6.2 mL, 43.5 mmol), and the reaction stirred at 0° C., for 5 min, rt for 1 h. Reaction diluted with DCM (700 mL), washed with 0.1N HCl (700 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 10-60% hexanes/EtOAc to afford the title compound as a yellow oil (5.73 g, 39% yield).
Reaction SMILES: [Na].[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH:5](P(OCC)(=O)OCC)[NH:4]1.[CH3:17][C:18]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([N+:27]([O-:29])=[O:28])[C:19]=1[CH:20]=O>C(O)C.O>[CH3:17][C:18]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([N+:27]([O-:29])=[O:28])[C:19]=1[CH:20]=[C:5]1[NH:4][C:3](=[O:2])[NH:7][C:6]1=[O:8]
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1C
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])c(C=C2NC(=O)NC2=O)c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium (0.41 g, 0.018 g atom) was dissolved in ethanol (40 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (4.21 g, 18 mmol) added. After 5 minutes, 2,3-dimethyl-6-nitrobenzaldehyde (2.66 g, 15 mmol) was added in one portion and the mixture stirred at room temperature for 90 minutes. The mixture was diluted with water, filtered and the solid washed with water and air dried gave 5-[(2,3-dimethyl-6-nitrophenyl)methylene]-2,4-imidazolidinedione as a single geometrical isomer (3.35 g, 86%). Analytical sample prepared by crystallization from methanol had m.p. 293°-295° C.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].CCOCC>C(Cl)(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[CH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CCC(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC2CCC(C(C)(C)O[SiH2]C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
To a 100 mL-flask containing 83 (3.4 g, 13.2 mmol) in CHCl3 (30 mL) was added tosyl chloride (3.26 g, 17.1 mmol) and pyidine (3.2 mL, 39.6 mmol). The reaction was allowed to stir at 25° C. for 14 hours after which time the reaction was concentrated in vacuo to yield a wet white solid. To this solid was added ether (50 mL) and the solid was filtered and subsequently washed with additional ether (2×50 mL) The ether layers were pooled, concentrated in vacuo to yield a clear oil which was purified by flash chromatography, on a silica gel column, eluting with 1:4 ether/petroleum ether to yield 84 (4.5 g, 83%) as a white solid. 1H NMR (CDCl3) δ 7.78 (d, J=7.7, 2H), 7.33 (d, J=7.7 Hz, 2H), 3.81 (d, J=6.2 Hz, 2H), 3.37 (d, J=6.2, 2H), 2.44 (s, 3H), 1.95-1.72 (m, 4H), 1.65 (m, 1H), 1.40 (m, 1H), 1.03-0.89 (m, 4H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3) δ 145.1, 133.7, 130.3, 128.4, 75.8, 68.9, 40.7, 38.0, 29.1, 26.5, 22.1, 18.9, −4.9; APCI m/z (rel intensity) 413 (MH+, 100).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se-:9][Se-:10].[Mg+2].Cl>O>[CH2:1]([Se:9][Se:10][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: [Se-][Se-]
Agent: Cl
Agent: [Mg+2]
Solvent: O
Product: c1ccc(C[Se][Se]Cc2ccccc2)cc1

Procedure:
About 12.6 grams (0.1 moles) benzylchloride is now added by dropwise addition over a period of 15 minutes to the magnesium diselenide reagent. In about 5 to 10 minutes after the mixture of these materials, the reddish brown color of the solution appears discharged. This solution is diluted further by the addition of 200 milliliters water and the addition of 10 milliliters concentrated hydrochloric acid. Upon cooling of this solution, the solids contained within the flask are collected by filtration and recrystallized from ethanol. Yield: 14 grams of yellow crystals (m. p. 94° C.). Infrared spectral analysis of this material confirms that it is dibenzyl diselenide.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:16].[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([NH:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:16])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Solvent: c1ccncc1
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](CNC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
5′-Amino-2′,5′-dideoxyuridine (0.200 g, 0.88 mmol) was taken in dry pyridine (5 mL) and the mixture was sonicated for a few minutes. Trityl chloride (0.278 g, 1.00 mmol) was added and the reaction mixture was stirred at 50° C. overnight. The reaction was then quenched with water (20 mL). The crude mixture was extracted with DCM (3×10 mL). The organic layers were combined, washed with water (10 mL), dried over MgSO4 and concentrated on the rotary evaporator. The resultant brown oil was further purified by silica gel column chromatography (Isolute Si column) using a gradient elution of 0→10% CH3OH in CHCl3. The fractions with Rf=0.28 (10% CH3OH/CHCl3) were pooled and evaporated to dryness to yield the title compound as a white solid (0.202 g, 49%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N[C:9]1([O:18]O)[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10]1.S([O-])([O-])(=O)=O.[Mg+2]>S(=O)(=O)(O)O.C(O)C>[C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][CH:13]1[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9](=[O:18])[CH2:14]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: O=C1CCCCC1
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 0.17 h

Procedure:
To a stirred mixture of cyclohexanone (19.6 g) and ethanol (50 c.c.), kept at or below 0°C, was added 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (17.3 g, 78% pure); solution was complete in ca. 10 min. To the solution was added conc. sulphuric acid (3 drops) and magnesium sulphate and the mixture was stored at 0°C for 3 days. The solid was filtered off, the filtrate washed with water, dried and distilled, to give cyclohexanone, dihydroisophorone and a fraction (11.5 g), b.p. 90°-100° at 0.02 mm Hg, peroxide equivalent 179. By mass spectroscopy the product was shown to contain the unsymmetrical peroxide ##SPC3##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[N:26][CH:27]=1)(=[O:21])=[O:20].C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[C:5]3[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:25]=[N:26][CH:27]=1)(=[O:21])=[O:20]
Reactant: Brc1ccc2nccc(-c3ccncc3)c2c1
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cncc(-c2ccc3nccc(-c4ccncc4)c3c2)c1
Temperature: 25 °C

Procedure:
A mixture of (6-bromo-4-(4-pyridinyl)quinoline (250 mg, 0.88 mmol), 5-methylsulfonyl pyridine-3-boronic acid (201 mg, 1.0 mmol), tetrakistriphenylphosphine palladium(0) (104 mg, 0.09 mmol), and sat. aqueous NaHCO3 (1.75 mL), in dioxane (5 mL) was heated at 110° C. for 1 h then cooled to room temperature. The rxn was filtered through Celite and Na2SO4 onto silica and the crude product was purified by column chromatography (5% EtOAc/Hex-10% Ethanol/EtOAc; 30 min gradient). Evaporation and precipitation from MeOH/water (2/98) provided the title compound as a yellow solid. (160 mg, 50%). ESMS [M+H]+=362.1
Reaction SMILES: FC1C=CC(C=O)=CC=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14](/[CH:15]=[N:16]\[OH:17])=[CH:13][CH:12]=1.[Cl:20]N1C(=O)CCC1=O>CN(C=O)C>[OH:17]/[N:16]=[C:15](\[Cl:20])/[C:14]1[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O/N=C\c1ccc(Cl)cc1
Agent: O=Cc1ccc(F)cc1
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of (E)- and/or (Z)-4-chloro-benzaldehyde oxime 4-fluorobenzaldehyde (27.0 g, 173 mmol) in DMF (173 mL) was added N-chlorosuccinimide (22.8 g, 173 mmol) portionwise over 1 h, keeping the temperature below 35° C. The reaction mixture was stirred at room temperature for 1 h. The mixture was then poured onto ice-water, and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound (28.4 g, 86%) which was obtained as a light yellow solid. MS: m/e=189.1 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:9][CH3:10])[CH2:8][CH2:7][S:6][CH2:5][CH2:4]1.CO.COC1CCSCC=1.OC1C(O)=[C:29]([O:32][CH3:33])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>CC1C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[CH3:33][O:32][C:29]1[C:1]2[O:2][C:3]3([O:9][C:10]=2[C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=1)[CH2:8][CH2:7][S:6][CH2:5][CH2:4]3
Reactant: COc1ccc(C(=O)O)c(O)c1O
Reactant: COC1(OC)CCSCC1
Agent: COC1=CCSCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)O)c2c1OC1(CCSCC1)O2
Temperature: 145 °C
Yield: 60.4 %

Procedure:
P-Toluenesulfonic acid (97 mg, 0.51 mmol) was added to 4,4-dimethoxytetrahydro-(4H)-thiopyran (20.7 g, 128 mmol) and the mixture was heated to 145° C. and kept at that temperature until approximately one equivalent of methanol (5.17 mL, 128 mmol) was distilled off. The mixture was then cooled to 130° C. and distillation under reduced pressure afforded 10.1 g of a 5:3 mixture of 5,6-dihydro-4-methoxy-(2H)-thiopyran [1H NMR (DMSO) δ 4.87 (m, 1H), 3.44 (s, 3H), 3.15 (dt, 2H), 2.72 (t, 2H), 2.22 (m, 2H)] and 4,4-dimethoxytetrahydro-(4H)-thiopyran. Without further purification the mixture was added to 2,3-dihydroxy-4-methoxybenzoic acid (2.00 g, 10.9 mmol) and the suspension was exposed to microwave heating (180° C., one hour) in a sealed reaction vessel. Ethyl acetate (100 mL) was added and the organic phase was first washed with 0.5 M HCl (40 mL) and then extracted with saturated aqueous NaHCO3 (2×30 mL). The aqueous phase was washed with Et2O (2×40 mL), acidified to pH=1 with concentrated HCl and extracted with dichloromethane (2×30 mL). The organic phase was dried over MgSO4. Evaporation under reduced pressure afforded 7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-carboxylic acid (1.86 g, 61%). 13C NMR (DMSO) δ 164.9, 148.2, 146.6, 134.5, 123.8, 118.0, 107.2, 106.9, 56.1, 35.9, 25.4.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:19](O)=[O:20])=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.[F:22][C:23]1[CH:32]=[C:31]([NH2:33])[CH:30]=[C:29]([F:34])[C:24]=1[C:25]([O:27][CH3:28])=[O:26].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:22][C:23]1[CH:32]=[C:31]([NH:33][C:19]([C:6]2[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]3[C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10][C:9]([CH3:18])([CH3:17])[C:8]=3[CH:7]=2)=[O:20])[CH:30]=[C:29]([F:34])[C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1c(F)cc(N)cc1F
Reactant: COCOc1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCOc1cc2c(cc1C(=O)Nc1cc(F)c(C(=O)OC)c(F)c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methoxymethoxy-5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid (Compound K, as described in U.S. Pat. No. 5,856,490, 112mg, 0.38 mmol) in 6 ml of anhydrous methylene chloride was added 4-(dimethylamino)pyridine (DMAP, 100 mg, 0.46mmol), methyl 2,6-difluoro-4-aminobenzoate (Compound H1, as described in U.S. Pat. No. 5,856,490, 77mg, 0.38mmol ) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 110 mg, 0.57 mmol). The reaction mixture was stirred at room temperature for overnight then concentrated to dryness. The residue was purified by column chromatography with ethyl acetate: hexane (1:9) to yield the title compound as a clear oil.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:12][Si:13]([CH3:40])([CH3:39])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2[N:23]=[CH:24][N:25]=[C:26]([C:27]3[CH:28]=[N:29][N:30]([C:32]4([CH2:36][C:37]#[N:38])[CH2:35][NH:34][CH2:33]4)[CH:31]=3)[C:21]=2[CH:20]=[CH:19]1.Cl[C:42]1[N:43]=[CH:44][C:45]([C:48]([NH:50][C@@H:51]([CH3:56])[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:37]([CH2:36][C:32]1([N:30]2[CH:31]=[C:27]([C:26]3[C:21]4[CH:20]=[CH:19][N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:39])([CH3:12])[CH3:40])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:28]=[N:29]2)[CH2:33][N:34]([C:42]2[N:43]=[CH:44][C:45]([C:48]([NH:50][C@@H:51]([CH3:56])[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=2)[CH2:35]1)#[N:38]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: C[C@H](NC(=O)c1cnc(Cl)cn1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1)C(F)(F)F
Temperature: 120 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
N,N-Diisopropylethylamine (0.11 mL, 0.62 mmol) was added to a mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (110 mg, 0.22 mmol) and 5-chloro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide (52 mg, 0.21 mmol) in NMP (3.0 mL). The reaction mixture was stirred at 120° C. for 2 h. The reaction mixture was worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethylene (0-65%) to afford the desired product (100 mg, 73%). LCMS (M+H)+: m/z=627.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1O
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCCO)o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccccc1OCCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol (1.32 g), 2-methylphenol (865 mg), tributylphosphine (1.21 g) and tetrahydrofuran (30 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.51 g) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[4(2-methylphenoxy)butyl]oxazole was obtained as crystals (1.61 g, 96%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction. Recrystallization from acetone-isopropyl ether gave colorless prisms. Melting point 71-72° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[N:6][C:7](=O)[NH:8][CH:9]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:13]>CN(C)C1C=CC=CC=1>[Cl:13][C:7]1[N:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1cnc(=O)[nH]c1
Solvent: CN(C)c1ccccc1
Product: CC(C)c1cnc(Cl)nc1

Procedure:
A mixture of 5-isopropylpyrimidin-2(1H)-one (2.1 g, 15.2 mmol), POCl3 (15 ml), and N,N-dimethylaniline (5 drops) was heated at reflux under a nitrogen atmosphere for 2 h. Upon cooling, the majority of the POCl3 was removed under reduced pressure. The residue was poured into ice water and extracted with chloroform (3×20 ml). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated to provide 2-chloro-5-isopropylpyrimidine as a light brown oil, which was used without further purification.
Reaction SMILES: [CH3:1][P:2]1(=[O:7])[CH2:6][CH2:5][CH:4]=[CH:3]1.[CH3:8][PH:9](=[O:11])[CH3:10]>C(OCCCC)(=O)C1C(=CC=CC=1)C(OCCCC)=O>[CH3:1][P:2]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]1[P:9](=[O:11])([CH3:10])[CH3:8]
Reactant: CP1(=O)C=CCC1
Reactant: C[PH](C)=O
Solvent: CCCCOC(=O)c1ccccc1C(=O)OCCCC
Product: CP(C)(=O)C1CCCP1(C)=O

Procedure:
116 g of 1-methyl-1-oxophospholine and 6 g of tert.-butyl perpivalate in dibutyl phthalate are added dropwise with stirring under an oxygen-free atmosphere to 234 g of dimethyl phosphine oxide. The reaction temperature is 75° to 80° C. The starting materials are then distilled off. The residue consists of 185 g of 1-methyl-1-oxophospholanyl dimethyl phosphine oxide.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].[SiH:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17]>O1CCCC1>[CH2:16]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:17]
Reactant: CC[SiH](CC)CC
Reactant: CSc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)CSc1ccccc1
Yield: 67.9 %

Procedure:
The reaction was conducted according to the General Procedure by heating thioanisole (62 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11 mg, 0.1 mmol, 0.2 equiv) and Et3SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 65 hours at 65° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica using hexanes (isochratic) to obtain 81 mg (68%) of the title compound as a colourless oil. 1H NMR (500 MHz, THF-d8) δ 7.31-7.26 (m, 2H), 7.25-7.19 (m, 2H), 7.11-7.01 (m, 1H), 1.03 (t, J=7.9 Hz, 9H), 0.78-0.60 (m, 6H). 13C NMR (126 MHz, THF-d8) δ 140.73, 128.31, 125.69, 124.19, 13.01, 6.62, 3.06. HRMS: [C13H21SSi] calculated 237.1140. measured 237.1133. The HSQC spectra of the thioanisole and its reaction product as provided in FIGS. 7A and 7B.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]3=[O:22])=[CH:11][C:10]=2[F:23])[CH2:5][CH:4]1[F:24].CSC.C(Cl)(=O)C>>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]3=[O:22])=[CH:11][C:10]=2[F:23])[CH2:5][CH:4]1[F:24]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1F
Solvent: CC(=O)Cl
Solvent: CSC
Product: O=C1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1F
Temperature: 40 °C
Reaction time: 96 h
Yield: 54 %

Procedure:
To the mixture of (R)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-alcohol (0.726 mmol), freshly fused zinc chloride (2.17 mmol), dimethyl sulphide (3.2 mmol), acetyl chloride (2.17 mmol) in tetrahydrofuaran (50 ml) was stirred at 40° C. for 4 days. To this reaction mixture extracted with the ethyl acetate water mixture and organic layer was dried over sodium sulfate. The removal of the solvent afforded a residue, which was chromatographed over silica gel afforded title compound in 54% yield.