Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[NH:10]2)=[CH:5][CH:4]=1.I[CH3:24]>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[N:10]2[CH3:24])=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)cc1
Reactant: CI
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)cc1
Temperature: 100 °C
Yield: 75.2 %

Procedure:
A mixture of (4S,7R)-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 40; 300 mg, 1.0 mmol) and iodomethane (315 μL, 5.1 mmol) in dimethylformamide (9 mL) was heated in a sealed tube at ˜100° C. for 1 h 40 min. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane (100 mL), transferred to a round-bottomed flask and evaporated. Ethyl acetate (100 mL) and dichloromethane (50 mL) were added and the solution was washed with water, concentrated aqueous sodium thiosulfate (50 mL; 50% w/v), saturated aqueous sodium hydrogen carbonate (50 mL) and brine (50 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified using a Biotage 40S system, eluting with 3% methanol/dichloromethane. Fractions homogeneous for the product were evaporated, co-evaporated with ethanol and dried under high vacuum to give (4S,7R)-2-(4-methoxy-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (235 mg, 75%) as an off-white solid. APCI(+)-MS (M+H) 313.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17]([OH:19])=O)=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12.[Cl:20]CCCl.CN(C)C=O.S(Cl)(Cl)=O>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17]([Cl:20])=[O:19])=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12
Reactant: ClCCCl
Reactant: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)O
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)Cl
Temperature: 90 °C
Yield: 78 %

Procedure:
To a solution of 4 g (12.9 mmol) of 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carboxylic acid 40 mL of 1,2-dichloroethane and 0.1 mL dimethyl formamide was carefully added 4.7 mL (64.4 mmol) of thionyl chloride. The reaction was heated to 90° C. for five hours. The reaction was cooled to room temperature and dry ethyl ether was added. The resulting brown precipitate was collected by vacuum filtration, washed with diethyl ether and dried to afford 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carbonyl chloride (3.31 g) in 78% yield. C12H6Cl2N2OS2: APCI m/z (in methanol to give methyl ester) 325.1/327.1 (pos.); 1H NMR (d6-DMSO): δ 8.68 (d, 1H, J=5.0 Hz), 8.32 (s, 1H), 8.65 (d, 1H, J=5.0 Hz), 2.39 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[C:22]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:13][CH2:12][CH2:11][NH:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:31]2[CH2:32][CH2:33][CH:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)[N:3]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:5]=1
Reactant: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCc2cccnc2)nc1N1CCC(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 47b, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile (example 49a) was treated with 4-phenyl-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield 4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperidin-1-yl)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, brownish powder; MS: [M+H]+=430.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:30]([F:33])([F:32])[F:31])=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27](O)=O)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[OH:47][NH:48][C:49](=[NH:53])[CH:50]([CH3:52])[CH3:51]>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[CH:50]([C:49]1[N:53]=[C:27]([CH:24]2[CH2:23][CH2:22][N:21]([C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:10]4[N:11]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[O:8][C:9]=4[C:30]([F:32])([F:31])[F:33])=[O:13])=[CH:20][CH:19]=3)[CH2:26][CH2:25]2)[O:47][N:48]=1)([CH3:52])[CH3:51]
Reactant: CC(C)C(=N)NO
Reactant: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1noc(C2CCN(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid (200 mg, 0.435 mmol) in 2 mL of CH2Cl2 was added a drop of DMF and approximately 2 mL of oxalyl chloride dropwise (gas evolution observed). The resulting mixture was stirred at room temperature for 72 hours, then concentrated to produce a solid, which was triturated with ether, then suspended in 5 mL of THF. To this suspension was added triethylamine (110 mg, 151 μL, 1.088 mmol), followed by N-hydroxy-isobutyramidine (54 mg, 0.529 mmol). The resulting reaction mixture was stirred at room temperature overnight, then diluted with EtOAc, and washed twice with saturated NH4Cl solution. The organic phase was then dried over Na2SO4, filtered, and concentrated. The residue was re-dissolved in 5 mL of THF, and treated with 4 N TBAF solution in THF (excess, ca. 2 mL). The mixture was stirred at room temperature overnight, and then diluted with EtOAc. The organic phase was washed with water, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography on silica gel (gradient elution with 10-50% ethyl acetate in hexanes) to produce 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-phenyl}-amide as an off-white solid. HRMS calcd for C27H26F3N5O3 (M+H) 526.2061, obsd 526.2059.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([I:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CN(C=O)C.C(OC)(C)(C)C.O.COC1C=CC(CCl)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:5]=[C:6]([I:8])[CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1cc(Br)cc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(Br)cc(I)c2)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 77.8 %

Procedure:
3-Bromo-5-iodo-phenol (8.48 g, 28.37 mmol) was dissolved in DMF (50 mL) under dry argon and cooled to 0° C. Then potassium carbonate (3.92 g, 28.37 mmol) was added, followed by drop wise addition of 4-methoxybenzyl chloride (3.7 mL, 27.0 mmol). The mixture was slowly warmed to room temperature and stirred for 20 h. Additional 4-methoxybenzyl chloride (0.19 mL, 1.4 mmol) was added and the mixture was stirred for additional 24 h at room temperature. The reaction mixture was diluted with tert-butylmethyl ether (300 mL) and water (150 mL). The layers were separated and the aqueous one extracted with tert-butylmethyl ether (2×150 mL). The combined organics were washed with water and brine (150 mL), dried (Na2SO4) and concentrated to give the crude product which was purified by flash chromatography on silica gel (330 g, AcOEt/heptane 1:9). 1-Bromo-3-iodo-5-(4-methoxy-benzyloxy)-benzene (8.80 g, 59%, purity 80%, HPLC 220 nm) was obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: Fc1ccccc1-c1cncc(N2CC3CC4CC2CN(C4)C3)c1

Procedure:
The title compound was prepared from the product of Example 65A and 2-fluorophenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 324.0 (M+H)+, retention time 1.30 minutes.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:23][CH3:24])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:9])=[O:2].CC(C)=[O:27].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>O>[CH3:24][O:23][C:6]1[CH:5]=[CH:4][C:3]([C:1]([OH:27])=[O:2])=[CH:22][C:7]=1[C:8](=[O:9])[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1
Reactant: CC(C)=O
Reactant: COc1ccc(C=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(C(=O)O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reaction time: 0.42 h

Procedure:
To 500 mg of 5-formyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide were added 20 ml of acetone and 0.5 ml of Jones reagent under cooling with ice, and the mixture was stirred for 25 minutes. Then, 0.2 ml of Jones reagent were added further and the mixture was stirred for 35 minutes. To the reaction mixture were added 100 ml of water, which was extracted (100 ml×2) with methylene chloride (small quantity of acetone was added). After washed with 50 ml of saturated brine, the organic layer was dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel, methylene chloride:methanol=100:1, quantity of methanol was increased gradually), then recrystallized from hexane-acetone to obtain 270 mg of aimed product as white crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].C([Li])CCC.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1.O>[C:14]1([CH2:13][CH:3]2[CH2:4][CH2:5][CH2:6][NH:1][C:2]2=[O:7])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCCN1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1NCCCC1Cc1ccccc1
Temperature: -40 °C
Reaction time: 12 h
Yield: 53.9 %

Procedure:
To a stirred solution of 2-piperidone (40 g, 0.404 mol) in tetrahydrofuran (800 ml) at 0° C. was added, over a period of 2 hours, n-butyl lithium (2.5 M in hexane, 356 ml, 0.889 mol). The reaction was cooled to -40° C. and a solution of benzyl bromide (48 ml, 0.404 mol) in tetrahydrofuran (200 ml) was added dropwise over a period of 2 hours. The reaction was allowed to warm slowly to room temperature and stirred for 12 hours. Water (100 ml) and saturated aqueous ammonium chloride (100 ml) were added and the aqueous phase separated and extracted with ethyl acetate (3×100 ml). The combined organic phases were washed with brine (200 ml), dried with sodium sulphate and evaporated in vacuo. The resulting solid was recrystallised from toluene to give the desired product as white needles (41.2 g), m.pt. 120°-123° C. Low resolution mass spectroscopy revealed the mass/charge ratio of the parent molecule ion, M+, to be 190 thereby confirming the molecular of the product to be 190.
Reaction SMILES: Cl[C:2]([C:4]1[S:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1)=[O:3].[C:13]([CH:15]1[CH2:17][CH2:16]1)#[CH:14]>C(N(CC)CC)C.CO.[Cu]I>[CH:15]1([C:13]#[C:14][C:2]([C:4]2[S:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=2)=[O:3])[CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(C(=O)Cl)s1
Reactant: C#CC1CC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C(=O)C#CC2CC2)s1
Reaction time: 8 h

Procedure:
Methyl 5-(chlorocarbonyl)thiophene-2-carboxylate (500 mg, 2.443 mmol) was dissolved in triethylamine (5 mL) and the suspension was degassed with nitrogen. Copper(I) iodide (40 mg, 0.210 mmol) and bistriphenylphosphine palladium chloride (40 mg, 0.057 mmol) were added followed by ethynylcyclopropane (162 mg, 2.443 mmol). The mixture was stirred overnight, diluted with methanol and concentrated to dryness. The crude material was partitioned between dichloromethane and water. The organic extracts were dried with sodium sulfate, filtered, concentrated and purified by normal phase chromatography to afford the title compound.
Reaction SMILES: [OH:1][CH:2]1[O:6][C@H:5]2[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]2[CH2:3]1.[CH3:12][C:13](O)([CH3:15])[CH3:14].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[C:13]([O:1][CH:2]1[O:6][C@H:5]2[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]2[CH2:3]1)([CH3:15])([CH3:14])[CH3:12]
Reactant: CC(C)(C)O
Reactant: O=CC1=C[C@H]2CC(O)O[C@H]2C1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC1C[C@@H]2C=C(C=O)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Partially purified residue containing lactol 7, was dissolved in CH2Cl2 (40 ml) and stirred at r.t. t-BuOH (2.58 g, 3.33 ml, 34.8 mmol, 2.0 eq. based on ˜14% of 7 detected by internal standard in the previous reaction) was added via syringe. Amberlyst 15 (249 mg) and MgSO4 (5.15 g) were added as solids in one portion and the reaction mixture was stirred at r.t. for 14 h. The reaction was charged with further portions of t-BuOH (2.58 g, 3.33 ml, 34.8 mmol, 2.0 eq.), Amberlyst 15 (249 mg) and MgSO4 (5.15 g) and stirred for a further 24 h. The reaction mixture was filtered through a sinter funnel and the solids washed with CH2Cl2 (2×15 ml). The filtrate was concentrated under reduced pressure and purified by column chromatography (˜50 g silica), eluting with petrol/EtOAc (4:1), to give the t-butyl acetal 52, (as an approximately 2:1 mixture of diasteroisomers (635 mg, 2% (over 2 steps from succinaldehyde, 17% from lactol 7))) as a yellow oil.
Reaction SMILES: [CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C@@H:13]4[C:18]([CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:22])=[CH:17][C:16](=[O:21])[CH2:15][CH2:14]4)[CH2:2][CH3:3].[C:23](Cl)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C@@H:13]4[C:18]([CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:17][C:16](=[O:21])[CH2:15][CH2:14]4)[CH2:2][CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Product: CCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OCc1ccccc1

Procedure:
Esterify 13β-propyl-17β-hydroxy-gon-4-en-3-one (2.5 g.) with benzoyl chloride (2.0 g.). Purify the product by chromatography on Florex and recrystallize from ethyl acetate to obtain the title compound, m.p. 198°-200°; ultraviolet absorption peak at 240 mμ (ε25,000); infrared absorption peaks at 5.84, 6.00 μ.
Reaction SMILES: C[Mg]Br.[CH:4]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([CH3:16])=[CH:12]2)([CH3:6])[CH3:5].[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].[NH4+].[Cl-]>CCOCC.C1COCC1>[CH:4]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([CH3:16])=[C:12]2[C:20]([C:19]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:18]=1[Cl:17])=[O:21])([CH3:6])[CH3:5]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: Cc1cc2cccc(C(C)C)c2[nH]1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1[nH]c2c(C(C)C)cccc2c1C(=O)c1cccc(Cl)c1Cl
Temperature: -30 °C
Reaction time: 1 h

Procedure:
120 ml of anhydrous THF are cooled to −5° C. and 36 ml of 3M methylmagnesium bromide in ether are added. The mixture is cooled to −30° C. and then 15 g of 7-isopropyl-2-methyl-1H-indole are added dropwise. The mixture is left stirring for 1 hour between −20° C. and −30° C. and then 30.9 g of 2,3-dichlorobenzoyl chloride, dissolved in 120 ml of THF, are added dropwise. The medium is left to return to AT and is then poured onto 300 ml of a saturated NH4Cl solution. Separation is carried out by settling, the organic layer is evaporated and then the residue is taken up in DCM. The organic phase is washed with a saturated NaCl solution and then it is dried and evaporated. The residue is chromatographed on silica while eluting with an AcOEt/cyclohexane (3/7, v/v) mixture.
Reaction SMILES: O=[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].[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].[C:18]([OH:23])(=[O:22])[C:19]([OH:21])=[O:20]>O1CCOCC1.C(O)C>[C:18]([OH:23])(=[O:22])[C:19]([OH:21])=[O:20].[CH2:13]([NH:17][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4])[CH2:14][CH2:15][CH3:16]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCN
Agent: O=C(O)C(=O)O
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCNCC(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 70 °C

Procedure:
18 g of D-glucose are suspended in 200 ml of dioxane and 100 ml of ethanol, and 7.3 g of butylamine are added. The mixture is warmed to 70° C. and, after 10 minutes, 9.0 g anhydrous oxalic acid is added. The temperature is maintained for 4 hours. After cooling to room temperature, the product crystallizes out. The solid is filtered off with suction, rinsed five times with 50 ml of ethanol each time and dried in vacuo.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:10][CH2:9][CH2:8]1)[C:3]([O:5][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: O=C(O)[C@@H](O)CC1CCC1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@@H](O)CC1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
A mixture of 1.05 g (7.3 mmol) of 2-(S)-hydroxy-3-(cyclobutyl)propanoic acid (from Step D), 40 mL (10.0 mmol) of TEA and 1.20 mL (10.0 mmol) of benzyl bromide in 8 mL of DMF was stirred at rt for 2 h. The mixture was partitioned between 200 mL of ether and 100 mL of H2O and the layers were separated. The organic layer was washed with 100 mL of 2.0 N HCl, 100 mL of sat'd NaHCO3, 2×100 mL of H2O, 100 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography on 60 g of silica gel using 4:1 v/v hexanes/ether as the eluant afforded 1.20 g (70%) of the title compound: 1H NMR (500 MHz) δ 1.58-1.70 (m, 2H), 1.72-1.82 (m, 2H), 1.84-1.92 (m, 2H), 1.98-2.10 (m, 2H), 2.46-2.58 (m, 1H), 2.63 (br s, 1H), 4.15 (dd, J=7.5, 3.0), 7.33-7.40 (m, 5H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:8][C:9]2[CH:14]=[C:13]([C@H:15]3[C@H:20]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@@H:19]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:18]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:17]([CH2:45][O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[O:16]3)[CH:12]=[CH:11][C:10]=2[Cl:54])=[CH:6][CH:7]=1.[CH3:55][N:56](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:54][C:10]1[CH:11]=[CH:12][C:13]([C@H:15]2[C@H:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@@H:19]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:18]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@@H:17]([CH2:45][O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[O:16]2)=[CH:14][C:9]=1[CH2:8][C:5]1[N:4]=[N:3][C:2]([C:55]#[N:56])=[CH:7][CH:6]=1
Reactant: Clc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)nn1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)nn1
Yield: 52 %

Procedure:
Intermediate 6 (compound 24, 4.0 g, 5.3 mmol) was added to a microwave reaction tube containing zinc cyanide (0.93 g, 7.9 mmol) and tetrakis(triphenylphosphine) palladium(0) (1.2 g, 1.1 mmol) in N,N-dimethylformamide (30 mL). The capped reaction tube was placed in a microwave reactor (Biotage® Initiator™) and the mixture was irradiated at 160° C. for 15 min. After dilution with ethyl acetate, the organic layer was subsequently washed with water, 10 wt % potassium carbonate and brine prior to drying over magnesium sulfate. After filtration and concentration under reduced pressure, the residue was purified on a Biotage® purification apparatus (silica gel, 10 to 60% ethyl acetate in hexanes gradient) to yield the title compound (2.0 g, 2.7 mmol, 52%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[C:13]([C:15]1[S:19][CH:18]=[N:17][CH:16]=1)=[O:14]>>[S:19]1[C:15]([C:13]([N:1]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:2]2[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:14])=[CH:16][N:17]=[CH:18]1
Reactant: CCOC(=O)C1CCCCN1
Reactant: O=C(Cl)c1cncs1
Product: CCOC(=O)C1CCCCN1C(=O)c1cncs1

Procedure:
Ethyl N-(5-thiazolylcarbonyl)pipecolinate is prepared as in Example 1, from 4.4 g of ethyl pipecolinate and 5.25 g of 5-chloroformylthiazole. 7.7 g of ethyl N8(5-thiazolylcarbonyl)pipecolinate are thus obtained in the form of brown oil. (Rf=0.51; thin layer chromatography on silica gel; eluent: 55/45 dichloromethane/ethyl acetate).
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)#[CH:2].[CH2:8]([O:10][C:11](=[O:15])/[CH:12]=[CH:13]\I)[CH3:9]>>[CH2:8]([O:10][C:11](=[O:15])[CH:12]=[CH:13][C:2]#[C:1][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH3:9]
Reactant: CCOC(=O)/C=C\I
Reactant: C#Cc1cccs1
Product: CCOC(=O)C=CC#Cc1cccs1

Procedure:
The general procedure was used to convert 2-Ethynyl-thiophene and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (10% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (230 mg, 62% yield). 1H NMR (400 MHz, CDCl3) δ 7.36-7.35 (dd, J=5.1, 1.0, 1H), 7.33-7.32 (dd, J=3.6, 1.0, 1H), 7.02-7.00 (m, 1H), 6.36-6.33 (d, J=11.4, 1H), 6.10-6.08 (d, J=11.4, 1H), 4.29-4.23 (q, J=7.1, 2H), 1.36-1.32 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 164.79, 133.49, 129.19, 127.62, 127.36, 122.57, 122.29, 94.50, 90.82, 60.51, 14.31. Anal. Calcd. for C11H10O2S: C, 64.05; H, 4.89; S, 15.55; Found C, 64.01; H, 4.95; S, 15.27.