Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[N:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O>C1COCC1.O.CO>[C:18]([C:15]1[N:14]=[CH:13][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1)#[N:19]
Reactant: CCOC(=O)C1CCN(c2ccc(C#N)nc2)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(N2CCC(C(=O)O)CC2)cn1
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a stirred solution of 6′-cyano-3,4,5,6-tetrahydro-2H-[1,3]bipyridinyl-4-carboxylic acid ethyl ester (1.61 g, 6.20 mmol) in THF (30 mL), H2O (30 mL) and MeOH (3 mL) was added LiOH.H2O (326 mg, 7.76 mmol). Stirring was continued overnight at RT before the organic solvent were removed under vacuo. The pH of the was adjusted to 5 with acetic acid, and the product extracted with EtOAc, dried over Na2SO4. The resulting solid was suspended in heptane, filtered off, washed with cold Et2O to give 1.40 g (99%) of 6′-cyano-3,4,5,6-tetrahydro-2H-[1,3]bipyridinyl-4-carboxylic acid. ES-MS m/e: 230.1 (M−H+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([NH:23]C(OCC=C)=O)=[C:21]([NH:30][CH2:31][CH:32]3[CH2:40][CH2:39][C:35]4([CH2:38][CH2:37][CH2:36]4)[CH2:34][CH2:33]3)[N:20]=[C:19]([C:41]#[N:42])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([NH2:23])=[C:21]([NH:30][CH2:31][CH:32]3[CH2:40][CH2:39][C:35]4([CH2:38][CH2:37][CH2:36]4)[CH2:34][CH2:33]3)[N:20]=[C:19]([C:41]#[N:42])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOC(=O)Nc1c(NCC2CCC3(CCC3)CC2)nc(C#N)nc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(NCC3CCC4(CCC4)CC3)c2N)CC1
Reaction time: 1 h

Procedure:
To a solution of the crude 4-(2-{5-allyloxycarbonylamino-2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester (230 mg) in THF (10 mL) are added trietylamine (1.25 mmol) and Pd(PPh3)4 (catalytic amount) at room temperature under N2 atmosphere. After stirring at the same temperature for 1 h, the reaction mixture is diluted with AcOEt. The organic layer is washed with H2O and evaporated in vacuo. The resulting residue is purified by silica gel column chromatography to give 4-(2-{5-Amino-2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester; 1H-NMR (CDCl3), δ: 0.97-1.07 (2H, m), 1.13-1.28 (4H, m), 1.42-1.88 (25H, m), 2.69 (2H, t), 3.22 (2H, s), 3.31 (2H, t), 4.04-4.16 (2H, m), 4.40 (2H, t), 4.51 (1H, t).
Reaction SMILES: C1(B(O)O)C=CC=CC=1.C(C1C=CC(B(O)O)=CC=1)CCC.[CH2:23]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:37]=[CH:36][O:35][C:34]=2[C:38]([NH:40][NH2:41])=[O:39])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26].C([O:45][C:46]1[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][C:47]=1[N+:55]([O-:57])=[O:56])(=O)C.CCN=C=NCCCN(C)C>C(Cl)(Cl)Cl.CN(C=O)C>[OH:45][C:46]1[CH:54]=[CH:53][C:49]([C:50]([NH:41][NH:40][C:38]([C:34]2[O:35][CH:36]=[CH:37][C:33]=2[C:30]2[CH:29]=[CH:28][C:27]([CH2:23][CH2:24][CH2:25][CH3:26])=[CH:32][CH:31]=2)=[O:39])=[O:51])=[CH:48][C:47]=1[N+:55]([O-:57])=[O:56]
Reactant: CCCCc1ccc(-c2ccoc2C(=O)NN)cc1
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CCCCc1ccc(B(O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: OB(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc(-c2ccoc2C(=O)NNC(=O)c2ccc(O)c([N+](=O)[O-])c2)cc1
Reaction time: 2 h

Procedure:
A reaction and treatment was carried out in the same manner as in Reference Example 14 except that the phenylboronic acid used in Reference Example 14 was replaced with 4-butylphenylboronic acid, thereby giving 3-(4-butylphenyl)-2-furancarboxylic acid hydrazide. This 3-(4-butylphenyl)-2-furancarboxylic acid hydrazide (1.62 g), 4-acetoxy-3-nitrobenzoic acid (compound of Reference Example 80, 1.66 g), WSC (1.50 g) and DMF (25 ml) were stirred at 25° C. for 2 hours. The reaction solution was diluted with chloroform and successively washed with water, 20% citric acid solution, aqueous saturated sodium hydrogencarbonate solution and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. After dissolving the residue in ethanol (15 ml), 2 M aqueous sodium hydroxide solution (16 ml) was added at 25° C. and stirred for 2 hours. The reaction solution was neutralized with hydrochloric acid solution and extracted with ethyl acetate. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was recrystallized from acetonitrile, thereby giving 1.80 g of the desired compound.
Reaction SMILES: [C:1]([C:3]1[O:4][CH:5]=[CH:6][CH:7]=1)#[N:2].C[O-].[Na+].[C:11](O)(=[O:13])C>CO>[O:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:1](=[NH:2])[O:13][CH3:11]
Reactant: CC(=O)O
Reactant: N#Cc1ccco1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccco1
Temperature: 25 °C
Yield: 1844.3 %

Procedure:
2-Cyanofuran (4.50 9, 48.3 mmol) was dissolved in methanol (25 ml), and sodium methoxide (130 mg, 2.4 mmol) was added under ice-cooling. The mixture was stirred while the temperature is slowly raised up to room temperature for 2 hours. After the reaction was completed, acetic acid (0.16 g, 2.6 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Diethyl ether (100 ml) was added to the concentrated residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl 2-furancarboximidate (6.0 g) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[CH:16]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1cccc(F)c1)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 3-fluorobenzyl bromide (1.0 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 291 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([OH:9])[CH2:3]1.N1C=CC=CC=1.[C:17](Cl)(=[O:21])/[CH:18]=[CH:19]/[CH3:20].O>C(OC)(C)(C)C>[C:17]([O:9][CH:4]1[CH2:5][CH:6]([CH3:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3]1)(=[O:21])/[CH:18]=[CH:19]/[CH3:20]
Reactant: CC1CC(O)CC(C)(C)C1
Reactant: C/C=C/C(=O)Cl
Solvent: O
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: C/C=C/C(=O)OC1CC(C)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
71 g of 3,3,5-trimethylcyclohexanol having a cis content of 90% are placed in a 1-l reaction flask together with 60 g of pyridine in 300 ml of methyl tert-butyl ether and 63 g of crotonic acid chloride are added at 0 to 5° C. over 30 minutes. The reaction mixture is left to continue reacting for a further one hour at this temperature; it is then allowed to heat up to room temperature. After one hour it is heated for a further 30 min to 50° C. After cooling, it is fractionated with water, the organic phase is separated off and first washed with dilute hydrochloric acid and then stirred for a further 30 min with 5-percent sodium hydroxide solution. After washing until it is neutral, the solvent is drawn off and the residue distilled using a short column. 63 g of pure 3,3,5-trimethylcyclohexyl crotonate having a cis content of 90% are obtained at a boiling point of 121° C. under 20 mbar. MS: 210 (M*, 0,3), 195 (0,5), 141 (3), 124 (75), 109 (100), 95 (24), 87 (24), 82 (25), 69 (75), 55 (11), 41 (33). The cis-3,3,5-trimethylcyclohexyl esters of propionic acid, isobutyric acid and butyric acid can be prepared in an analogous manner.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[CH:9]([CH3:10])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(C)C(O)c1ccc(F)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C)C(=O)c1ccc(F)cc1

Procedure:
To a solution of 1-(4-Fluoro-phenyl)-2-methyl-propan-1-ol (1.6 g) in acetone (10 mL) at 0° C. is added Jones reagent (20 mL) with stirring. After 10 minutes excess Jones reagent is destroyed by addition of isopropyl alcohol. Diethyl ether is added followed by anhydrous magnesium and the mixture is filtered and evaporated to give the product, a yellow oil (1.2 g).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(O)(=O)C.C(N(CC)CC)C.[CH:35]1([C:38]2[N:43]=[C:42]([C:44](=N)OCC)[CH:41]=[CH:40][N:39]=2)[CH2:37][CH2:36]1>C(O)C>[CH:35]1([C:38]2[N:43]=[C:42]([C:44]3[NH:10][C:9]4=[N:8][C:7]([N:11]5[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]6[CH2:23][CH2:22][CH2:21][CH2:20]6)=[O:18])[CH2:12]5)=[CH:6][CH:5]=[C:4]4[N:3]=3)[CH:41]=[CH:40][N:39]=2)[CH2:37][CH2:36]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)c1ccnc(C2CC2)n1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1)N1CCCC1
Temperature: 40 °C

Procedure:
To a suspension of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (1.0 g, 2.76 mmol) and acetic acid (2.5 mL, 43.4 mmol) in ethanol (7 mL) was added triethylamine (1.5 mL, 10.8 mmol). A solution of ethyl 2-cyclopropylpyrimidine-4-carbimidate (530 mg, 2.77 mmol) in ethanol (3 mL) was added. The reaction mixture was heated at reflux for 30 min, then was cooled. The solvent was removed under reduced pressure and ethyl acetate (100 mL) was added to the residue followed by water (10 mL) and a saturated aqueous solution of ammonium chloride (50 mL). The layers were separated and the organics were washed with a saturated aqueous solution of sodium bicarbonate (75 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. To the resulting residue was added dichloromethane (4 mL) and methyl tert-butyl ether (35 mL). The mixture was stirred at 40° C. unit it was homogeneous. The solution was cooled to room temperature and stirred for 18 h. The resulting solids were filtered and rinsed with ether to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 1.10-1.17 (m, 2H) 1.18-1.23 (m, 2H), 1.57-1.70 (m, 1H) 1.82-2.05 (m, 7H) 2.27-2.34 (m, 1H) 2.63-2.72 (m, 1H) 2.97-3.07 (m, 1H) 3.14-3.22 (m, 1H) 3.43-3.54 (m, 3H) 3.58-3.67 (m, 1H) 4.37 (d, 1H) 4.53 (d, 1H) 6.76 (d, 1H) 7.95 (m, 2H) 8.67 (d, 1H) 10.46 (br, 1H). MS (ES+) (M+H) 418.5; LCMS retention time 2.72 min (Method L).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH3:10])[C:4]=1[CH3:11].[OH:12]O>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N+:6]([O-:12])=[C:5]([CH3:10])[C:4]=1[CH3:11]
Reactant: OO
Reactant: COc1c(C)cnc(C)c1C
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1c(C)c[n+]([O-])c(C)c1C
Temperature: 90 °C

Procedure:
100 g 4-methoxy-2,3,5-trimethylpyridine was dissolved in 300 ml glacial acetic acid and 100 ml 50% hydrogenperoxide and stirred at 30° C. for 1 h. The temperature was gradually heated to70° C. and was maintained for 5 hrs and the temperature increased to 90° C. and a small amount of Pd/C added to destroy excess hydrogenperoxide. After testing that the peroxide was destroyed the solvents were evaporated at reduced pressure. Toluene was added and stripped off to make the product free from water. After the product was dry most of the toluene was evaporated in vacuum. The 4-methoxy-2,3,5-trimethylpyridine N-oxide was diluted with acetic acid and used directly in the next step. The yield of N-oxide was 95%.
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](SC)=[N:15][C:14](=[O:21])[N:13]([CH2:22][CH2:23][CH3:24])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[NH2:25][C@H:26]([CH2:29][CH3:30])[CH2:27][OH:28]>CS(C)=O>[OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16]([NH:25][CH:26]([CH2:27][OH:28])[CH2:29][CH3:30])=[N:15][C:14](=[O:21])[N:13]([CH2:22][CH2:23][CH3:24])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: CCCn1c(=O)nc(SC)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Reactant: CC[C@@H](N)CO
Solvent: CS(C)=O
Product: CCCn1c(=O)nc(NC(CC)CO)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Temperature: 150 °C
Reaction time: 3 h

Procedure:
8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-6-methylsulfanyl-3-propyl-3,7-dihydro-purin-2-one (125 mg, 0.36 mmol) was dissolved in 3 mL of DMSO along with an excess of an appropriate amino alcohol (e.g., (R)-(−)-2-amino-1-butanol (0.24 mL, 7 eq) for compound 2). The resulting reaction mixture was stirred at 150° C. for 3 h. It was then cooled to rt and purified by preparative HPLC to afford 110 mg of the titled compound.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[C:7](Cl)(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>[OH-].[Na+].CCOCC>[C:7]([N:1]([CH3:2])[CH2:3][C:4]([OH:6])=[O:5])(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CNCC(=O)O
Reactant: CCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCCC(=O)N(C)CC(=O)O
Reaction time: 1 h
Yield: 100.9 %

Procedure:
Sarcosine (1.78 g, 20 mmol) was dissolved in 1N NaOH solution (40 ml) and Et2O (40 ml) was added. After cooling in an ice bath a solution of hexanoyl chloride (3.1 ml, 22 mmol) in Et2O (10 ml) was added dropwise. The mixture was stirred cold for 1 hour. The pH was then adjusted to about 8 by adding 1N NaOH solution (about 3 ml) and the mixture was stirred at room temperature 45 minutes. NaOH solution was added to about pH 9-10. The layers were separated and the aqueous layer was washed with Et2O (50 ml). After acidification of the aqueous layer with concentrated HCl and saturation with solid KCl, the product was extracted into CHCl3 (3×70 ml). The combined CHCl3 extracts were washed with saturated NaCl solution (25 ml), dried (MgSO4), and freed of solvent leaving the title compound as an oil (3.78 g, quant.) which was used without further purification.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH:24]2[CH2:26][CH2:25]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH:24]1([C:16]2[N:15]([CH:12]3[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH2:11]3)[C:23]3[C:18]([CH:17]=2)=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:26][CH2:25]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2c(C3CC3)cc3ccccc32)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC1CCC(n2c(C3CC3)cc3ccccc32)CC1
Reaction time: 72 h

Procedure:
Crude 1-[4-(tert-butyldimethylsilanyloxy)cyclohexyl]-2-cyclopropyl-1H-indole from above (10.4 mmol) was dissolved in tetrahydrofuran (150 mL), and tetrabutylammonium fluoride (21 mL, 1 M in THF, 21 mmol) was added. After the reaction was stirred for 72 hours it was concentrated and the residue partitioned between ethyl acetate and water. The organic layer was dried (MgSO4), concentrated and purified by SiO2 chromatography (10-50% ethyl acetate/hexanes) to give two (cis/trans) isomers (355 mg of the more polar isomer, 681 mg of the less polar isomer) of the desired alcohol. LC-MS (C17H21NO calc'd 255) m/z 256 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].C(N(CC)C(C)C)(C)C.[NH2:26][C@@H:27]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:26][C@H:27]([CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (159 mg, 0.62 mmol), N,N-diisopropylethylamine (0.54 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 45% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (231 mg, 0.44 mmol, 71% yield) as a clear oil: LCMS (ES) m/e 525, 527 (M, M+2)+.
Reaction SMILES: Br[CH2:2][C:3](=[O:7])[C:4]([OH:6])=[O:5].[N-:8]=[N+:9]=[N-:10].[Na+]>CS(C)=O>[N:8]([CH2:2][C:3](=[O:7])[C:4]([OH:6])=[O:5])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)C(=O)CBr
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
KY-740 3-bromo-2-oxopropanoic acid (1.66 gr, 10 mmol) was added to a solution of sodium azide (0.715 gr, 11 mmol) in DMSO (20 ml) which was prepared by stirring the sodium azide in DMSO at room temperature for 40 min. the mixture reaction was stirred for 2 h at room temperature. It was quenched with water (50 ml). The mixture was extracted with Et2O (3×100 ml). The combined organic layers were washed with water, dried with Na2SO4, filtered, and concentrated in vacuo. Yield 1.1 gr (85%). 1HNMR (400 MHz, DMSO-d6) δ 6.3 (s, 2H). 13C-NMR δ 113.52, 136.31, 165.3.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C(=O)([O-])[O-:14].[Na+].[Na+]>>[CH2:11]([OH:12])[C@@H:9]([OH:10])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C:3]([C:2]([OH:14])=[O:1])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 5.71 %

Procedure:
The catalyst Pt/Pb/C with Pt/Pb ratio of 5/1.5 is used. The D-glucose solution (5% d.s.) is heated at 55° C., pH is brought to 8 by adding sodium carbonate and the procedure of example 1 is followed. Already in 28 minutes equimolar amounts of alkali are consumed and only 5.71% 2-keto-D-gluconic acid is formed.
Reaction SMILES: C(OC(=O)[CH2:5][NH:6][CH2:7][CH2:8][N:9]([C:22]([O:24]C(C)(C)C)=O)[CH2:10][CH2:11][C:12]1[CH:21]=[CH:20][C:15]2[C:16](=[O:19])[O:17][CH2:18][C:14]=2[CH:13]=1)C.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C>>[O:19]=[C:16]1[C:15]2[CH:20]=[CH:21][C:12]([CH2:11][CH2:10][N:9]3[CH2:8][CH2:7][NH:6][CH2:5][C:22]3=[O:24])=[CH:13][C:14]=2[CH2:18][O:17]1
Reactant: CCOC(=O)CNCCN(CCc1ccc2c(c1)COC2=O)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCc2cc(CCN3CCNCC3=O)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask charged with Ethyl[(2-{(tert-butoxycarbonyl)[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}ethyl)amino]acetate (280 mg, 0.69 mmol) and a stir bar was added TFA (2 mL). The mixture was allowed to stir at RT for 1 hour. The solvent was removed under vacuum, and the residue was dissolved in EtOH (5 mL). To the solution was added Hunig's base (0.36 mL, 2.1 mmol), and the solution was heated to 150° C. in a microwave tube for 45 minutes. LC showed mostly product, which was purified by silica gel chromatography (MeOH-DCM). The adduct was treated with 4N HCl to remove the BOC group and provide the title compound. LC-MS (IE, m/z): 261 [M+1]+.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[S:41]1[CH:45]=[CH:44][C:43]([CH:46]=O)=[CH:42]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][CH2:46][C:43]1[CH:44]=[CH:45][S:41][CH:42]=1)[CH2:19][CH2:18]2
Reactant: O=Cc1ccsc1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCc3ccsc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (30 mg, 0.055 mmol) in DCE (0.5 mL) was added 3-thiophenecarboxaldehyde (7.73 mg, 0.069 mmol) and titanium(IV) isopropoxide (0.020 mL, 0.069 mmol). The mixture was stirred at rt for 1 h and sodium triacetoxyborohydride (23.38 mg, 0.110 mmol) was added. The mixture was stirred for 18 h at rt. The reaction mixture was loaded directly onto a silica gel column and was purified by flash chromatography using a 0-25% EtOAc in hexanes gradient. The fractions containing the expected product were combined and were concentrated under reduced pressure to give the title compound (32 mg, 0.05 mmol, 91% yield). LCMS: m/e 640.6 (M+H)+, 2.13 min (method 2).