Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13].C(O[C:18]([C:20]1([OH:28])[CH2:25][CH2:24][N:23]([O:26][CH3:27])[CH2:22][CH2:21]1)=[O:19])C.CC(C)([O-])C.[K+]>C1COCC1>[OH:19][C:18]1[C:20]2([CH2:21][CH2:22][N:23]([O:26][CH3:27])[CH2:24][CH2:25]2)[O:28][C:3](=[O:2])[C:4]=1[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13]
Reactant: CCOC(=O)C1(O)CCN(OC)CC1
Reactant: COC(=O)Cc1cc(C)c(C)cc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CON1CCC2(CC1)OC(=O)C(c1cc(C)c(C)cc1C)=C2O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2,4,5-trimethyl-phenyl)acetic acid methyl ester (0.6 g, 3.12 mmol) and 4-hydroxy-1-methoxy-piperidine-4-carboxylic acid ethyl ester (0.76 g, 3.74 mmol) in 7 ml anhydrous THF was added a 1 M solution of potassium tert-butoxide (6.9 ml, 8.87 mmol) in THF at room temperature. The suspension obtained was first stirred at room temperature for one hour, and then refluxed under argon for one hour. After cooling to room temperature, the reaction mixture was concentrated, water was added and the mixture acidified with little HCl (37%). The aqueous layer was extracted with dichloromethane, and the combined organic layers were then washed with brine and dried over sodium sulfate. After filtration and concentration under vacuum, the residue was purified by column chromatography (silica gel, ethyl acetate 100%). Yield: 280 mg of 4-hydroxy-8-methoxy-3-(2,4,5-trimethyl-phenyl)-1-oxa-8-aza-spiro[4.5]dec-3-en-2-one (title compound P2.2) as a white solid, mp 199-204° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([NH:12][C@H:13]2[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[C@@H:17]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:16]([CH3:37])[O:15][C:14]2=[O:38])=[O:11])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:39](Cl)(=[O:41])[CH3:40].CCN(CC)CC>CN(C1C=CN=CC=1)C.ClCCCl>[C:39]([O:1][C:2]1[C:3]([C:10](=[O:11])[NH:12][C@H:13]2[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[C@@H:17]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:16]([CH3:37])[O:15][C:14]2=[O:38])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9])(=[O:41])[CH3:40]
Reactant: COc1ccnc(C(=O)N[C@H]2CCC[C@H](Cc3ccc(C)cc3)[C@@H](Oc3ccccc3)[C@H](C)OC2=O)c1O
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccnc(C(=O)N[C@H]2CCC[C@H](Cc3ccc(C)cc3)[C@@H](Oc3ccccc3)[C@H](C)OC2=O)c1OC(C)=O
Temperature: 50 °C
Yield: 69.9 %

Procedure:
A 25 mL screw top vial was charged with 3-hydroxy-4-methoxy-N-((3S,7R,8R,9S)-9-methyl-7-(4-methylbenzyl)-2-oxo-8-phenoxyoxonan-3-yl)picolinamide (74.0 mg, 0.143 mmol), DMAP (19.4 mg, 0.159 mmol), 1,2-dichloroethane (DCE; 1 mL), acetyl chloride (20 μL, 0.281 mmol), and NEt3 (70 μL, 0.502 mmol). The resulting mixture was heated to 50° C. for 7 h. After cooling to room temperature, the crude reaction mixture was directly purified by column chromatography on SiO2 (2→40% acetone/hexanes) to provide the title compound as a white solid (56.0 mg, 70%): mp 96-100° C.; 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J=8.4 Hz, 1H), 8.33 (d, J=5.5 Hz, 1H), 7.36-7.27 (m, 2H), 7.12-6.92 (m, 8H), 5.12 (dq, J=9.1, 6.4 Hz, 1H), 4.63 (dt, J=10.9, 7.5 Hz, 1H), 4.33 (t, J=8.9 Hz, 1H), 3.89 (s, 3H), 2.97 (dd, J=13.3, 3.2 Hz, 1H), 2.41 (s, 3H), 2.32 (d, J=9.3 Hz, 5H), 2.14-2.03 (m, 1H), 1.73-1.48 (m, 3H), 1.39-1.19 (m, 5H); 13C NMR (101 MHz, CDCl3) δ 172.55, 168.83, 162.34, 159.62, 159.36, 146.65, 141.31, 137.42, 137.01, 135.34, 129.62, 128.96, 128.61, 121.12, 115.50, 109.76, 81.10, 74.64, 56.22, 51.52, 45.62, 36.35, 33.75, 26.67, 20.95, 20.69, 18.83, 18.31; ESIMS: m/z 561 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=1.C(#N)C.C1C(=O)N([Br:20])C(=O)C1>>[Br:20][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:9]
Reactant: COc1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(Br)c(C)c1
Temperature: 10 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 122 g (1.0 mol) of 1-methoxy-3-methylbenzene in 1 L of acetonitrile 178 g (1.0 mol) of NBS was added in small portions by vigorous stirring for 1 h at 10° C. The reaction mixture was stirred at ambient temperature overnight and then evaporated to dryness. The residue was dissolved in 1 L of n-hexane and filtered through glass frit (G2). The precipitate was additionally washed by 2×150 ml of n-hexane. The combined filtrate was evaporated to dryness to give 173 g (86%) of 1-bromo-4-methoxy-2-methylbenzene.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[C:9]([O:13][CH3:14])=[CH:8][C:7](=[O:15])[C:6]=2[C:5]([OH:16])=[C:4]2[C:17](=[O:37])[C@:18]3([C:32]4[C:31]([OH:33])=[C:30]5[C:25]([CH:26]=[C:27]([CH:35]=O)[NH:28][C:29]5=[O:34])=[CH:24][C:23]=4[CH2:22][CH2:21]3)[C:19](=[O:20])[C:3]=12.[Cl-].[CH2:39]([O:46][NH3+:47])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.N1C=CC=CC=1.O>CN(C=O)C>[CH2:39]([O:46][N:47]=[CH:35][C:27]1[NH:28][C:29](=[O:34])[C:30]2[C:25]([CH:26]=1)=[CH:24][C:23]1[CH2:22][CH2:21][C@@:18]3([C:17](=[O:37])[C:4]4=[C:5]([OH:16])[C:6]5[C:7](=[O:15])[CH:8]=[C:9]([O:13][CH3:14])[C:10](=[O:12])[C:11]=5[C:2]([OH:1])=[C:3]4[C:19]3=[O:20])[C:32]=1[C:31]=2[OH:33])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)[C@]1(CCc2cc4cc(C=O)[nH]c(=O)c4c(O)c21)C3=O
Reactant: [NH3+]OCc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)[C@]1(CCc2cc4cc(C=NOCc5ccccc5)[nH]c(=O)c4c(O)c21)C3=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ten (10) mg (19.4 μmol) fredericamycin aldehyde (4) are dissolved in 2 mL DMF. After addition of 6.4 mg (43.2 μmol) O-benzylhydroxylammonium chloride and 3.2 μl pyridine, the reaction mixture is stirred for 2 h at room temperature. Then, it is added to 50 ml water, and the supernatant is sucked off from the red precipitate (HPLC clean).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].C([O-])([O-])[O-].C(=O)(O)[O-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[CH2:8]([O:7][CH:6]([O:10][CH2:11][CH3:12])[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:9]
Reactant: CCOC(OCC)OCC
Reactant: c1c[nH]cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(OCC)n1ccnc1
Yield: 63 %

Procedure:
A mixture of imidazole (15 g, 0.220 mol, 1 eq), triethyl orthoformate (130 g, 146.6 mL, 0.880 mol, 4.0 eq) and p-toluenesulfonic acid (1.17 g, 0.00616 mol, 0.028 eq) was heated at 145°-175° C. until no more ethanol was distillable from the reaction mixture. The excess orthoformate was removed in vacuo, solid sodium bicarbonate (1.17 g, 0.011 mol) was added and the residue was vacuum distilled to give the title compound (23.6 g, 68 %). b.p. 89°-91° C./0.3 mm Hg.
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[C:21](I)=[C:20]([CH3:26])[N:19]=1.[F:27][C:28]([F:51])([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[CH:29]=[CH:30][Sn](CCCC)(CCCC)CCCC>CN(C)C=O>[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[C:21]([CH:30]=[CH:29][C:28]([F:51])([F:27])[C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=2)=[C:20]([CH3:26])[N:19]=1
Reactant: CCCC[Sn](C=CC(F)(F)c1ccc(Cl)cc1)(CCCC)CCCC
Reactant: Cc1nc(N)nc(N)c1I
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(N)c1C=CC(F)(F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 0.04 gram (catalyst) of tri-2-furylphosphine and 0.04 gram (catalyst) of tris(dibenzylidineacetone)dipalladium(0) in 30 mL of N,N-dimethylformamide is purged with dry nitrogen gas and stirred at ambient temperature for five minutes. After this time 1.2 grams (0.0048 mole) of 2,4-diamino-5-iodo-6-methylpyrimidine (prepared in Step B of Example 3) is added in one portion. The reaction vessel is then immersed in an oil bath that is preheated to 60° C. where it is maintained for about five minutes. After this time, 3.1 grams (0.0064 mole) of 1,1-difluoro-1-(4-chlorophenyl)-3-tributylstannyl-2-propene is added in one portion to the reaction mixture. The reaction mixture is again purged with dry nitrogen gas, and the oil bath temperature is brought to 80°-85° C. where it is maintained for about 18 hours. After this time the reaction mixture is diluted with 200 mL of water and extracted with two 200 mL portions of ethyl acetate. The combined extracts are then washed with three 100 mL portions of an aqueous solution of 5% lithium chloride. The organic layer is concentrated under reduced pressure to a residue. The residue is purified by column chromatography, yielding 2,4-diamino-6-methyl-5-[3,3-difluoro-3-(4-chlorophenyl)-1-propenyl]pyrimidine.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][OH:12])=[CH:4][CH:3]=1.[C:13]([Cu])#[N:14].[C-]#N.[Na+]>CN1CCCC1=O>[C:13]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][OH:12])=[CH:4][CH:3]=1)#[N:14]
Reactant: N#C[Cu]
Reactant: OCC1CCc2ccc(Br)cc21
Agent: [C-]#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)C(CO)CC2
Temperature: 160 °C
Yield: 57 %

Procedure:
To a solution of 6-bromo-1-indanylmethanol (20 g) in N-methyl-2-pyrrolidone (NMP) (380 ml) was added CuCN (79 g). The mixture was heated at 160° C. for 6 hours. After cooling to 80-90° C. the mixture was poured into an aqueous solution (500 ml) of NaCN (4g). After stirring for 20 minutes excess CuCN was filtered off. Ethyl acetate (300 ml) was added and the organic phase was separated and worked-up. The remaining oil was dissolved in diethyl ether (300 ml) and washed with saturated brine (2×100 ml). The organic phase was separated and worked up according to the general procedure leaving 14.6 g of crude title compound 2a as a visceous oil. Column chromatography on silica gel (eluent:ethylacetat/heptane 6:4) afforded pure 2a (8.7 g) which was used without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>O1CCCC1>[C:8]1([S:7][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[CH2:23][OH:24])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccccc1SCCCCCCSc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccccc1SCCCCCCSc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of lithium aluminum hydride (0.292 g, 0.007 mole) in tetrahydrofuran (30 ml) is added a solution of 2-(6-thiophenoxyhexylthio)benzoic acid (2.42 g, 0.007 mole) in tetrahydrofuran (30 ml). The reaction is stirred at room temperature under argon, overnight. When the reaction is complete several drops of ice water are added followed by cold 10% sodium hydroxide (approximately 1.0 ml), followed by cold 10% sodium hydroxide (approximately 1.0 ml), followed by more ice water. This produces a dry granular precipatate which is filtered and is washed. The filtrate is then dried over magnesium sulfate, filtered and is evaporated. The crude alcohol is flash chromatographed on silica gel to give the desired compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22](I)=[N:23][C:24]=2[Cl:28])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH:37]#[C:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([C:37]#[C:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[N:23][C:24]=2[Cl:28])(=[O:3])[CH3:2]
Reactant: C#CCCCCCCC
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCCCCC#Cc1nc(Cl)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Yield: 89 %

Procedure:
In 12 ml of 1,4-dioxane were suspended 2.15 g (4 mmole) of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-iodopurine, 56 mg (0.08 mmole) of bis(triphenylphosphine)palladium dichloride and 15 mg (0.08 mmole) of cuprous iodide, and 1.2 ml of triethylamine and 0.75 ml of 1-nonyne were added to the suspension. The mixture was stirred and caused to react at room temperature (25° C.) for 12 hours. The reaction solution at this time had a transparent pale brown color, which was paler than those in the aforementioned (i) or (ii). After the reaction, the solution was concentrated, and 200 ml of ethyl acetate was added to the residue to obtain a solution, which was distributed and washed several times with an aqueous EDTA.2 Na solution and a saturated brine solution, respectively to remove copper ions. The organic layer was subjected to silica gel column chromatography in the same manner as in (i) to remove colored materials and other by-products and to produce 1.90 g (yield 89%) of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-(1-nonynyl)purine as a viscous material.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C(C)C.[CH:31]([C@H:33]1[CH2:38][CH2:37][C@H:36]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:35][CH2:34]1)=O.[Cl-].[NH4+]>CN(C)C=O>[CH3:1][CH:2]([CH3:5])/[CH:3]=[CH:31]\[C@H:33]1[CH2:38][CH2:37][C@H:36]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Reactant: CC(C)(C)[O-]
Agent: CC(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)/C=C\[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h

Procedure:
To a mixture of potassium t-butoxide (379 mg) and anhydrous N,N-dimethylformamide (20 ml) was added isobutyltriphenylphosphonium bromide (1.35 g) at room temperature. The mixture was stirred for 10 minutes, and then a solution of t-butyl trans-4-formylcyclohexyl-carbamate (700 mg) in N,N-dimethylformamide (3 ml) was added to the mixture. After the reaction mixture was stirred overnight, saturated aqueous ammonium chloride was added thereto. The mixture was extracted with toluene, and the organic layer was washed with brine, dried over sodium sulfate, and then the solvent was removed in vacuo. After diethyl ether was added to the residue, the precipitate was filtered off and then the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 380 mg of t-butyl trans-{4-[(Z)-3-methyl-1-butenyl]cyclohexyl}-carbamate.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH2:2][CH2:3][CH3:4].[CH3:19][NH:20][O:21][CH3:22].CN1CCOCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CCOC(C)=O>[CH2:1]([O:5][C:6]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:7]=1[C:8]([N:20]([O:21][CH3:22])[CH3:19])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CNOC
Reactant: CCCCOc1cc(C(F)(F)F)ccc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCCCOc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Yield: 103.1 %

Procedure:
2-Butoxy-4-trifluoromethyl-benzoic acid (687 mg) was reacted with N,O-dimethylhydroxy amine (331 mg), NMM (0.65 ml) and DMTMM (911 mg) as described above to yield the title compound (825 mg) after column chromatography (Hex/EtOAc=7.5/1).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][C:33]5[CH:34]=[N:35][CH:36]=[C:37]([F:39])[CH:38]=5)=[CH:27][C:26]=4[NH:41][C:42]4[C:43]5[CH:51]=[CH:50][C:49]([CH:52]([CH3:54])[CH3:53])=[N:48][C:44]=5[N:45]=[CH:46][N:47]=4)=[CH:20][CH:19]=3)C3C(=CC=CC=3)C=2C=CC=1.O.[OH-].[Li+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:32][C:33]3[CH:34]=[N:35][CH:36]=[C:37]([F:39])[CH:38]=3)=[O:40])=[CH:27][C:26]=2[NH:41][C:42]2[C:43]3[CH:51]=[CH:50][C:49]([CH:52]([CH3:54])[CH3:53])=[N:48][C:44]=3[N:45]=[CH:46][N:47]=2)=[CH:20][CH:19]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cncc(F)c4)ccc3Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)ncnc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cncc(F)c4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 70 °C
Yield: 61 %

Procedure:
A solution of the product of Example 224F (118.9 mg, 0.159 mmol) in 1,4-dioxane (3 mL) was treated with a solution of lithium hydroxide monohydrate (13.3 mg, 0.318 mmol) in water (1.5 mL) at ambient temperature, then heated at 70° C. for 45 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (30 mL), adjusted the aqueous pH to 6 with 1N aqueous hydrochloric acid, and separated the layers. The organic phase was washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Purification of the residue by silica gel chromatography eluting with 5% methanol/methylene chloride afforded the title compound as a yellow solid (51 mg, 61%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 3.10-3.34 (m, 1 H) 5.61 (s, 2 H) 6.64 (d, J=8.46 Hz, 2 H) 6.90 (d, J=8.09 Hz, 1 H) 7.15 (d, J=8.46 Hz, 2 H) 7.65 (d, J=8.09 Hz, 1 H) 7.81 (dd, J=7.17, 1.65 Hz, 1 H) 7.97 (s, 1 H) 8.13-8.23 (m, 1 H) 8.32 (d, J=2.57 Hz, 1 H) 8.59 (s, 1 H) 8.76 (d, J=1.47 Hz, 1 H) 8.89 (d, J=8.09 Hz, 1 H) 10.18 (s, 1 H) 10.59 (s, 1 H); MS (ESI+) m/z 526 (M+H)+, (ESI−) m/z 524 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>N1C=CC=CC=1.C(Cl)Cl>[C:30]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][N:20]=1)(=[O:31])[CH2:29][CH2:28][CH3:27]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccccc2)o1
Reaction time: 60 h
Yield: 97.5 %

Procedure:
To a solution of 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (200 mg, 0.54 mmol) in pyridine (1.0 mL) and CH2Cl2 (7.0 mL) was added n-butyryl chloride (84 μL, 0.81 mmol). Upon complete addition the reaction mixture was stirred for 60 h, then quenched with 10% aqueous HCl (10 mL). The mixture was partitioned between H2O (25 mL) and CH2Cl2 (30 mL). The aqueous layer was extracted with CH2Cl2 (25 mL). The combined organic extracts were washed with NaHCO3 (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide an orange viscous oil, which was purified by flash chromatography over silica gel (15-30% EtOAc in hexanes) to provide the title compound as a colourless solid (231 mg, 97%): 1H NMR (400 MHz, CDCl3, δ in ppm) 7.99 (td, J=1.4, 8.8 Hz, 2H), 7.57-7.47 (m, 3H), 7.38 (d, J=8.6 Hz, 2H), 6.73 (d, J=8.6 Hz, 1H), 5.59 (pentet, J=6.5 Hz, 1H), 5.19 (d, J=8.0 Hz, 1H), 5.03 (dd, J=5.9, 7.8 Hz, 1H), 2.34 (dt, J=2.3, 7.6 Hz, 2H), 2.31 (s, 3H), 1.64 (sextet, J=7.4 Hz, 2H), 1.37 (d, J=6.5 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CN(C)[C:17](=O)[CH3:18].C(=O)([O-])[O-].[K+].[K+].C(I)C>C(OCC)C.O>[CH2:17]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:18]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CCI
Product: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (5.0 g), N,N-dimethylacetamide (50 ml), potassium carbonate (5.3 g) and ethyl iodide (2.1 ml) were mixed, and the mixture was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature, water (100 ml) and ethyl ether (100 ml) were added, and the mixture was partitioned in a separatory funnel. The aqueous layer was further extracted with ethyl ether (100 ml), and the organic layers were combined. The organic layer was washed 3 times with water (100 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, hexane (50 ml) was added to the obtained residue and the mixture was partitioned in a separatory funnel. The organic layer was washed 3 times with water (40 ml) and once with saturated brine (40 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.1691 g, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(Cl)c1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(Cl)c1C(=O)Cl
Reaction time: 3 h

Procedure:
A round bottom flask containing the 2-chloro-6-methyl-benzoic acid (1.5 g, 8.79 mmol) and a stirring bar is charged with dry DCM (10 mL). Stirring is initiated. After several min, a solution of thionyl chloride (in DCM (2M), 6.6 mL, 13.2 mmol) is added via syringe. 2 drops of DMF are then added. The reaction immediately began to bubble gently. After 2 h bubbling ceases. After 3 h, the solvent is removed from the reaction mixture in vacuo. The oily residue is redissolved in DCM (6 mL) and the solvent once again removed in vacuo. The residue is dissolved in dry DCM (6 mL) and used without further purification in the next reaction sequence.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH2:9][CH2:10][CH3:11])CC(O)=O>>[C:14]1([CH2:13][CH2:12][C:4](=[O:3])[CH2:9][CH2:10][CH3:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCC(O)(CCc1ccccc1)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCC(=O)CCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
8.5 g of sodium hydroxide prills (213 mmol) in 100 ml of polyethylene glycol 1000 dimethyl ether (m.p.: 42° C.) were initially introduced at room temperature into a 3-necked flask having a dropping funnel, internal thermometer and stirrer. After 25 g of 3-hydroxy-3-(2′-phenylethyl)hexanoic acid (106 mmol), prepared according to K. S. Fors, J. R. Gage, R. F. Heier, R. C. Kelly, W. R. Perrault and N. Wicnienski, J. ORG. CHEM. 63, 7348 (1998), had been added, the mixture was heated to 80° C. for 10 min and then to 150° C. Thereafter, the pressure was reduced to 2.5 mbar and the mixture was stirred for 2 h at 150° C. and a pressure of 2.5 mbar, 1-phenylhexan-3-one formed by cleavage being collected in a cooled receiver. The 1-phenylhexan-3-one collected in the receiver was obtained, after washing with 20 ml of water, in a yield of 12.1 g (81% of theory) with a boiling point of 133° C. (13 mbar).