Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17](N)=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].NC1C=CC=CC=1>CC#N>[CH2:3]([C:17]1[CH:19]=[CH:20][C:14]([O:13][CH3:12])=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1)[CH:1]=[CH2:2]
Reactant: CC(C)(C)ON=O
Reactant: COc1ccc(N)cc1[N+](=O)[O-]
Solvent: Nc1ccccc1
Solvent: CC#N
Solvent: C=CCBr
Product: C=CCc1ccc(OC)c([N+](=O)[O-])c1
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 4-methoxy-3-nitroaniline (504 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 35-40° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 40° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. The crude product was dissolved in ethyl acetate-heptane (1:2, 20 ml) and filtered through a pad of silica. The solvent was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 97:3) gave 230 mg (40%) allyl-4-methoxy-3-nitrobenzene as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.45, (d, 1H, J=2.7 Hz), 7.27, (d, 1H, J=8.6 Hz), 7.10, (dd, 1H, J=8.6, 2.7 Hz), 6.02-5.90, (m, 1H), 5.12-5.02, (m, 2H), 3.86, (s, 3H), 3.62, (m, 2H, J=6.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 158.8, 150.0, 135.9, 133.2, 127.2, 120.2, 117.1, 109.6, 56.2, 36.8; Anal HRMS Calcd. for C10H11NO3 (M): 193.0739. Found: 193.0743
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:23]=[C:22]([CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:21]=[N:20][CH:19]=3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.CN(C)C=[O:43].[OH-].[K+]>CO>[OH:43][CH:24]([C:22]1[CH:21]=[N:20][CH:19]=[C:18]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][NH:11][C:12]3=[N:13][CH:14]=2)[N:23]=1)[C:25]([N:27]([CH3:29])[CH3:28])=[O:26]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cncc(CC(=O)N(C)C)n3)cc12
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cncc(C(O)C(=O)N(C)C)n3)cc12
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
Crude 2-{6-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrazin-2-yl}-N,N-dimethyl-acetamide (0.271 mmol) was dissolved in methanol (1 mL) and dimethylformamide (1 mL) and 50% w/v aqueous potassium hydroxide (0.5 mL) was added. After 30 minutes, the reaction was quenched by addition of acetic acid (0.5 mL). The mixture was carefully poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and dried to a residue which was purified by preparative HPLC to afford 2-hydroxy-2-{6-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrazin-2-yl}-N,N-dimethyl-acetamide (25 mg, 22.8%, 3 steps). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 2.32 (s, 3H), 2.78 (s, 3H), 3.79 (s, 3H), 5.37 (m, 1H), 5.61 (m, 1H), 7.03 (dt, J=7.0 Hz, 1H), 7.12 (br d, J=8.5 Hz, 1H), 7.29 (br dt, J=7.5 Hz, 1H), 7.57 (dd, J=7.5 Hz, 1H), 7.79 (br t, 1H), 8.47 (d, 1H), 8.61 (d, 1H), 8.65 (d, 1H), 8.75 (d, 1H). MS: m/z 404 (M+H+).
Reaction SMILES: Cl[CH:2]1[CH2:6][N:5]([CH2:7][CH3:8])[N:4]([CH2:9][CH3:10])[CH2:3]1.[OH-].[NH4+:12]>>[NH2:12][CH:2]1[CH2:6][N:5]([CH2:7][CH3:8])[N:4]([CH2:9][CH3:10])[CH2:3]1
Reactant: CCN1CC(Cl)CN1CC
Reactant: [NH4+]
Agent: [OH-]
Product: CCN1CC(N)CN1CC

Procedure:
A mixture of 100 g. (0.615 mole) of 4-chloro-1,2-diethylpyrazolidine and 200 ml. of concentrated ammonium hydroxide in a closed steel chamber was heated at 150° C. for approximately 36 hours. The cooled reaction mixture was extracted with isopropyl ether, the aqueous layer saturated with potassium carbonate and continuously extracted with chloroform for six hours. The dried chloroform extract (sodium sulfate) was concentrated at reduced pressure and the residue distilled at 113°-115° C./40 mm. to give 40.5 g. (45.5%) of product.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:15])=[C:6]([C:12](=[O:14])[CH3:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:2]=[CH2:3].[CH3:16][O:17][CH2:18][C:19](=O)[CH3:20].N1CCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]2[C:5]=1[O:15][C:19]([CH2:18][O:17][CH3:16])([CH3:20])[CH2:13][C:12]2=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OC)ccc(C(C)=O)c1O
Reactant: COCC(C)=O
Solvent: CC(=O)O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: C=CCc1c(OC)ccc2c1OC(C)(COC)CC2=O
Temperature: 25 °C
Yield: 32.5 %

Procedure:
445 mg of 3′-allyl-2′-hydroxy-4′-methoxyacetophenone and 0.57 g of methoxyacetone were dissolved in 10 ml of toluene. Thereafter, 0.19 g of pyrrolidine and 0.19 ml of acetic acid were added to the reaction solution. Thereafter, the reaction solution was heated to reflux using Dean-Stark for 1 hour. Thereafter, the reaction solution was cooled to a room temperature. 1.14 g of methoxyacetone, 0.38 g of pyrrolidine, and 0.38 ml of acetic acid were added to the reaction solution, and the obtained mixture was further heated to reflux overnight. The reaction solution was cooled to a room temperature and then concentrated under a reduced pressure. The residue was diluted with ethyl acetate, and then successively washed with 2 N hydrochloric acid, a 1 N sodium hydroxide aqueous solution, water, and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 194 mg of the subject compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2(O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].N1C=CC=CC=1.O>C(Cl)Cl>[Cl:3][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([Cl:5])[CH:7]=2)[NH:11][C:10]1=[O:15]
Reactant: O=S(Cl)Cl
Reactant: COc1ccccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reaction time: 0.5 h

Procedure:
38 ml (0.518 mol) thionyl chloride were slowly added by drops to 100 g (0.345 mol) of the intermediate product 1a, 56 ml (0.695 mol) pyridine in 1 l methylene chloride at 0° C., and then stirred for approximately 30 minutes more. Then the reaction mixture was poured on to icy water and the organic phase was separated. This organic phase was then washed with water, dried and concentrated in a vacuum. The residue was treated with toluene a number of times and the organic solvent was removed in a vacuum each time. 79 g of the raw product were obtained and further reacted without further cleaning.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:25]=[C:16]3[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][N:15]3[N:14]=2)=[CH:9][CH:8]=1.CN(C)[CH:28]=[O:29]>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:25]([CH:28]=[O:29])=[C:16]3[CH:17]=[CH:18][C:19]([C:21]([F:23])([F:22])[F:24])=[CH:20][N:15]3[N:14]=2)=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2cc3ccc(C(F)(F)F)cn3n2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 94 %

Procedure:
To a cold (0° C.) solution of phosphorus oxychloride (8.0 mL 86 mmol) in N,N-dimethylformamide (160 mL) was added 2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine (11.0 g, 39.3 mmol). The reaction mixture was stirred at room temperature for 72 hours, then quenched with ice water. The solid precipitate was collected on a filter to provide 2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (11.4 g, 94%) as a white solid. Rf 0.45 (4:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3): δ 10.15 (s, 1H), 8.92 (s, 1H), 8.53 (d, 1H), 7.80 (m, 2H), 7.70 (d, 1H), 7.27 (t, 2H); 19F NMR (CDCl3) δ −62.62, −110.62; MS m/z 307 (M−1).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[C:11]([CH3:28])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH3:27])([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:14][CH2:13]2.N1C=CN=C1>CN(C=O)C.C(=O)([O-])O.[Na+].C(OCC)C>[O:9]([C:10]1[C:11]([CH3:28])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH3:27])([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:14][CH2:13]2)[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)CC1(C)CCc2c(C)c(O[Si](C)(C)C(C)(C)C)c(C)c(C)c2O1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Under nitrogen, 5.41 g (35.9 mM) of tert-butyldimethylsilyl chloride was added to a solution of 7.69 g (27.63 mM) of methyl 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetate and 2.82 g (41.4 mM) of imidazole in DMF (54 ml) at room temperature and the mixture was stirred at 0° C. for 20 hours. This reaction mixture was poured in saturated aqueous sodium hydrogen carbonate-diethyl ether under intense agitation to stop the reaction and, then, extracted with diethyl ether. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (ethyl acetate-hexane: 10%) to provide the title compound as yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH2:10]([SH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([S:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N+:3]=1[O-:9]
Reactant: [O-][n+]1c(Cl)cccc1Cl
Reactant: CCCCCCCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCSc1cccc(Cl)[n+]1[O-]

Procedure:
The 2.01 g (0.0122 moles) of 2,6-dichloropyridine N-oxide and 2.10 g (85%) (0.0122 moles) of 1-octylmercaptan was reacted with 0.488 g (0.0122 moles) of ground sodium hydroxide in 8.2 ml of DMSO at 80° C. for 6 hours to give 2-chloro-6-octylthiopyridine N-oxide. It was reacted with 1.47 g (0.0367 moles) of ground sodium hydroxide at 80° C. for 3 hours to give 1-hydroxy-6-octylthiopyridine-2(1H)-one. After cooling, it was added 180 ml of water and was adjusted with 6N HCL to pH 3. The precipitate was filtered, washed with water and washed with 150 ml of petroleum ether to give 1.34 g (43%).
Reaction SMILES: C(NC(C)C)(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].[C:13]([O:24]C(C)(C)C)(=[O:23])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=O.[CH:29]([C:31]1[C:32]([NH:38]C(=O)C(C)(C)C)=[N:33]C(Cl)=CC=1)=O.[NH4+].[Cl-]>C(OCC)C.C1COCC1>[CH3:12][C:11]1[N:33]=[C:32]2[C:31]([CH:29]=[C:15]([CH2:14][C:13]([OH:24])=[O:23])[C:16](=[O:18])[NH:38]2)=[CH:9][CH:10]=1
Reactant: [Li]CCCC
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)ccc1C=O
Reactant: CC(C)(C)OC(=O)CCC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc2cc(CC(=O)O)c(=O)[nH]c2n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 24.9 %

Procedure:
To a precooled (−78° C.) solution of N,N-diisopropylamine (4.84 g, 48.0 mmol) in diethyl ether (125 mL, dried over molecular seives) was added BuLi (2.5 M in hexanes) (19.0 mL, 48.0 mmol), the solution was stirred at this temperature for 15 min before slow addition of di-tert-butyl succinate (5.75 g, 0.0250 mol) dissolved in diethylether (10 mL). After 20 min at −78° C., 3-formyl-6-chloro-2-(pivaloylamino)pyridine (5.00 g, 23.0 mmol) dissolved in dry THF (10 mL, LAB-SCAN C2520, dried over molecular seives) was slowly added. The resulting yellow solution was stirred at −78° C. for 30 min and then allowed to warm to rt. The solution was then poured into NH4Cl (sat., aqueous) (100 mL). The aqueous layer was separated and extracted with diethyl ether (3×50 mL, dried over molecular seives). The combined organic layers were washed once with water (50 mL) and once with brine (50 mL), dried over MgSO4, and evaporated in vacuo. The crude products of diastereomeric alcohols were dissolved in HCl (3M, aqueous) (80 mL) and refluxed for 3.5 h. The aqueous phase was washed with diethyl ether (3×75 mL, dried over molecular seives), with chloroform (3×50 mL) and then adjusted to pH 7 by addition of K2CO3. The resulting yellow precipitate was filtered off, washed once with water and once with diethylether and dried in vacuo to give the desired product (1.25 g, 27%) as a yellow solid. mp. >250° C. 1H NMR (D2O/NaOH; this compound exist as two rotamers; chemical shifts for the minor rotamer is given in brackets): δ 7.53 (d, 8.1 Hz, 1H), 7.31 (s, 1H), 6.69 (d, 8.1 Hz, 1H), 3.20 (s, 2H), 2.25 (s, 3H). 13C NMR (D2O/NaOH): δ 180.4, 172.1, 159.0, 155.7, 136.5, 135.9, 126.6, 116.6, 114.8, 39.6, 23.3. FAB+ MS (m/z): 218.0768 (M+H+, calc. for C11H10N2O3+H+ 219.0770).
Reaction SMILES: CO[SiH](OC)OC.[C:8]([O:13][CH2:14][CH2:15][CH2:16][Si](OC)(OC)OC)(=[O:12])[C:9]([CH3:11])=[CH2:10]>C1(C)C=CC=CC=1.C(Cl)C=C.[Pt]>[C:8]([O:13][CH2:14][CH:15]=[CH2:16])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Agent: [Pt]
Agent: CO[SiH](OC)OC
Solvent: Cc1ccccc1
Solvent: C=CCCl
Product: C=CCOC(=O)C(=C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A three-neck flask equipped with a reflux condenser, stirring rod and thermometer was charged with 50ml of toluene as a solvent, a small amount of polymerization inhibitor, 12.6 grams of allyl methacrylate ester (0.1 mole) and one cubic centimeter of Catalyst A of Example 1 as a catalyst (10-5 mole on a platinum basis). 13.4 grams of trimethoxy silane (0.11 mole) were dropwise added in one hour from a dropping funnel. The reaction temperature was maintained at about 50° C. The reaction was further carried out for 30 minutes. The gas chromatography analysis demonstrated that gamma-methacryloxypropyl trimethoxy silane was obtained in a yield of 86% on an allyl methacrylate basis.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)(=O)=O.[I-].[K+].[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][C:33]([NH2:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[ClH:22].[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][C:33]([NH:36][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH:17]1[CH2:18][CH2:19]1)([CH3:34])[CH3:35]
Reactant: CS(=O)(=O)OCCOc1ccccc1OCC1CC1
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(Cc1c[nH]c2ccc(Cl)cc12)NCCOc1ccccc1OCC1CC1
Product: Cl
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 160.4 %

Procedure:
2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate (8.0 g, 28.0 mmol) and potassium iodide (4.65 g, 28.0 mmol) were combined in DMF and the mixture was stirred at 120° C. for 15 minutes. [2-(5-Chloro-1H-indol-3-yl)-1,1-dimethyl-ethyl]amine (4.77 g, 21.7 mmol) and potassium carbonate (5.8 g, 42.0 mmol) were added to the mixture, which was then diluted with DMF (≈50 mL) and stirred at 130°-135° C. and under nitrogen for 2 hours. The mixture was cooled, poured into water (≈800 mL), and then extracted into ether. The organic phase was separated, washed once with water and then brine, dried over magnesium sulfate, and evaporated. The residue was dissolved in ethyl acetate, 5% hydrochloric acid in methanol was added, and the solution was evaporated. The residue was dissolved in ethyl acetate and a small amount of methanol and the solution was evaporated. The residue was again dissolved in ethyl acetate and methanol and the solution was evaporated. Filtration gave [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl][2-(2-cyclopropylmethyloxyphenoxy)ethyl]amine hydrochloride (7.8 g, 17.4 mmol), m.p. 199°-201° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:10][C@@H:11]1[C@@H:19]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:18](=[O:27])[O:17][CH2:16][C@H:15]([NH:28][C:29](=[O:39])[C:30]2[C:35]([OH:36])=[C:34]([O:37][CH3:38])[CH:33]=[CH:32][N:31]=2)[C:14](=[O:40])[O:13][C@H:12]1[CH3:41])(=[O:9])[CH:6]([CH3:8])[CH3:7].N1C=CC=CC=1>C(Cl)Cl>[C:5]([O:10][C@@H:11]1[C@@H:19]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:18](=[O:27])[O:17][CH2:16][C@H:15]([NH:28][C:29](=[O:39])[C:30]2[C:35]([O:36][C:1](=[O:3])[CH3:2])=[C:34]([O:37][CH3:38])[CH:33]=[CH:32][N:31]=2)[C:14](=[O:40])[O:13][C@H:12]1[CH3:41])(=[O:9])[CH:6]([CH3:7])[CH3:8]
Reactant: CC(=O)Cl
Reactant: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](CC3CCCCC3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](CC3CCCCC3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1OC(C)=O
Temperature: 22 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
Acetyl chloride (9 μL, 0.125 mmol) was added to a solution of (3S,6S,7R,8R)-8-(cyclohexylmethyl)-3-(3-hydroxy-4-methoxypicolinamido)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (50 mg, 0.100 mmol) and pyridine (40 μL, 0.480 mmol) in CH2Cl2 (1 mL), and the reaction was stirred at ambient temperature (about 22° C.) overnight. The solution was loaded directly onto a pre-packed SiO2 column for purification by column chromatography (0→30% EtOAc/CH2Cl2) to afford the title compound (28 mg, 52%) as a white solid: mp 164-170° C.; 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J=7.5 Hz, 1H), 8.35 (d, J=5.4 Hz, 1H), 7.03 (d, J=5.5 Hz, 1H), 5.47 (br s, 1H), 5.25-5.11 (m, 1H), 5.03 (t, J=9.9 Hz, 1H), 4.97-4.84 (m, 1H), 3.92 (s, 3H), 3.72 (br s, 1H), 2.69 (dd, J=16.8, 7.0 Hz, 1H), 2.60 (sept, J=14.0, 7.0 Hz, 1H), 2.40 (s, 3H), 1.83-1.54 (m, 6H), 1.36-1.02 (m, 14H), 0.94-0.67 (m, 2H); HRMS-ESI (m/z): calcd for C28H38N2O10, 562.2526; found, 562.2516.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[CH2:11]([OH:14])[CH2:12][CH3:13].[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1.[OH-].[Na+]>C1C=CC=CC=1.CCOCC.O>[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]([O:14][CH2:11][CH2:12][CH3:13])[O:8][CH2:16][CH2:15][CH3:20])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C=O)cc1
Reactant: CCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: C=Cc1ccc(C(OCCC)OCCC)cc1

Procedure:
In a 100 ml 3-necked round-bottomed flask, 6.8 g (51.5 mmol) of 4-vinylbenzaldehyde, 12.4 g (205.8 mmol) of n-propanol and 0.1 g (0.5 mmol) of p-toluenesulfonic acid are dissolved in 45 ml of benzene. The solution is refluxed for 22 hours using a water separator and then ether is added thereto. The mixture is subsequently neutralised with 0.1N sodium hydroxide solution. The organic phase is then washed three times with water, dried over magnesium sulfate and concentrated. The resulting oil can be purified by column chromatography (stationary phase silica gel, mobile phase hexane/ether 5/4) to yield 2.54 g (10.8 mmol, 21% of the theoretical yield) of the desired substance in the form of a clear oil.
Reaction SMILES: C(OC(=O)[CH:5]([CH:25]1[CH2:27][CH2:26]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH:22]1CC1)C(O)=O)C.C(Cl)(=O)C(Cl)=O.C[N:36]([CH:38]=[O:39])C.[C:40]([O:43][CH2:44][CH3:45])(=[O:42])C>ClCCl>[CH2:44]([O:43][C:40]([C:17]1([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:25]2([C:38](=[O:39])[NH2:36])[CH2:26][CH2:27]2)[CH2:18][CH2:22]1)=[O:42])[CH3:45]
Reactant: CCOC(C)=O
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(CCCCCCCCCCCCC(C(=O)O)C1CC1)C1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)C1(CCCCCCCCCCCCC2(C(N)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of product of Example 9 (1.5 g, 4.09 mmol) in dichloromethane (15 mL) was added oxalyl chloride (0.68 mL, 8.1 mmol) and catalytic amount of DMF (0.015 mL) at ice temperature. The ice bath was removed and reaction mixture stirred at room temperature over a period of 1 h. The crude product obtained upon evaporation of the solvent was diluted with DCM (10 mL), cooled to ice bath temperature and added ammoniated DCM (100 mL) drop wise fashion. Then reaction mixture was slowly allowed to reach room temperature and stirred for 2 h. The resulting reaction mass was diluted with ethyl acetate (250 mL), washed with water (100 mL×2) and dried over sodium sulphate. The residue obtained upon evaporation of the volatiles was purified by silica gel (230-400) column (40% ethyl acetate in petroleum ether) to give product as yellow oil 0.84 g (56%). The pale yellow oil solidified as off-white solid upon storage. mp: 49.5-51.2.2° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=2)[CH:3]=[N:2]1.[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[C:20]1([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CN(C(ON1N=N[C:37]2C=CC=N[C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[OH:26][C:20]1([C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:14]=2)[CH2:21][CH:22]2[N:23]([C:11]([C:8]3[CH:7]=[C:6]([C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[S:10][CH:9]=3)=[O:13])[CH:24]([CH2:36][CH2:37]2)[CH2:25]1
Reactant: OC1(c2ncccn2)CCNCC1
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1csc(-c2cn[nH]c2)c1)N1C2CCC1CC(O)(c1ncccn1)C2
Reaction time: 2 h

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.06 g, 0.31 mmol) and 4-pyrimidin-2-yl-piperidin-4-ol (0.082 g, 0.34 mmol) were dissolved in DMF (5 mL). HATU (0.13 g, 0.34 mmol) and diisopropylethylamine (0.32 mL, 1.85 mmol) were added and the resulting mixture was stirred for 2 hours. Aqueous sodium hydroxide (1 N, 3 mL) was added and the mixture stirred for 0.5 hours. The mixture was diluted with ethyl acetate and washed with brine, dried over magnesium sulphate, filtered and the solvent evaporated under vacuum. The residues were purified by HPLC on a C18 cartridge, eluting with 40%-70% methanol/water with 0.1% formic acid. The fractions containing the desired product were concentrated under vacuum and further lyophilised from methanol and water to give the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH:5]([O:7][C:8](=[O:30])[NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:11]([OH:22])[CH2:12][NH:13][CH2:14][C:15]([CH3:21])([CH3:20])[CH2:16][CH2:17][C:18]#[N:19])[CH2:4][O:3][CH2:2]1.[CH2:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(CC)(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[O:1]1[CH2:6][CH:5]([O:7][C:8](=[O:30])[NH:9][C@@H:10]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:11]([OH:22])[CH2:12][N:13]([CH2:14][C:15]([CH3:21])([CH3:20])[CH2:16][CH2:17][C:18]#[N:19])[S:45]([C:42]2[CH:41]=[CH:40][C:39]([O:38][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:44][CH:43]=2)(=[O:47])=[O:46])[CH2:4][O:3][CH2:2]1
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
{(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethyl-butylamino)-2-hydroxy-propyl}-carbamic acid[1,3]dioxan-5-yl ester (14.8 mg, 0.04 mmol) was combined with 4-benzyloxybenzenesulfonyl chloride (12.0 mg, 1.2 eq.) in anhydrous DMF (1 mL). Solution was chilled to 0° C. and N(i-Pr)2Et (18.4 μL, 3 eq.) was added. Reaction was allowed to warm to room temperature and stirred for 5 hours. Reaction mixture was diluted in EtOAc (10 mL) and washed with sat. NaHCO3 (10 mL), 0.5 N KHSO4 (10 mL) and brine (10 mL). Organic phase was dried with MgSO4 and solvent was removed in vacuo. Purification by preparative TLC (1:1, EtOAc:Hex). Recovered 4.2 mg (18%) of the product as a colorless residue. MS(ES); 666.2 (M+1), HPLC; tR=13.24 min. (98%).