Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[S:13]1[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[CH:15]=[CH:14]1.S1C2C=CC=NC=2C=C1.C1C[O:34][CH2:33]C1>O.CN(C)C=O.CCCCCC>[CH:33]([C:14]1[S:13][C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[CH:15]=1)=[O:34]
Reactant: c1cc2sccc2cn1
Reactant: C1CCOC1
Agent: [Li]CCCC
Agent: c1cnc2ccsc2c1
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc2cnccc2s1
Temperature: -25 °C

Procedure:
A solution of 1.6 g (15.8 mMoles) of diisopropylamine in 50 ml of dry THF was stirred under a nitrogen blanket and cooled to -25° C. The reaction solution was then diluted by the addition of 9.6 ml of a 1.6 Molar hexane solution of n-butyl lithium. The reaction mixture was stirred for twenty minutes at -25° C., and then was cooled to -70° C. and diluted by the dropwise addition of a solution of 1.7 g (13 mMoles) of thieno[3,2-c]pyridine in 50 ml of THF (temperature was maintained at -70° to -65° C. throughout the addition). Following complete addition of the thienopyridine, the reaction mixture was stirred at -70° C. for twenty minutes. A solution of 2.0 ml of N,N-dimethylformamide in 25 ml of THF was next added to the reaction mixture, and stirring was then continued at -70° C. for twenty minutes, and for an additional thirty minutes at -40° C. The reaction was quenched by the addition of 3 ml of glacial acetic acid, and then the mixture was warmed to 0° C. The reaction solvent was removed by evaporation under reduced pressure to provide the product as a crude oil. The oil was dissolved in water containing 1N hydrochloric acid to pH 1.0. The aqueous acid solution was extracted with dichloromethane, and then made alkaline to pH 11.5 with 1N sodium hydroxide. The alkaline solution was extracted several times with fresh dichloromethane, and the extracts were combined, dried, and the solvent was removed by evaporation under reduced pressure. Crystallization of the product thus formed from 500 ml of hot hexane afforded 800 mg of 2-formylthieno[3,2-c]pyridine.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:12]=[C:11](Cl)[C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([Cl:14])[CH:9]=2)[N:4]=1>O1CCCC1>[Cl:2][C:3]1[N:12]=[C:11]([NH2:1])[C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([Cl:14])[CH:9]=2)[N:4]=1
Reactant: COc1c(Cl)cc2c(Cl)nc(Cl)nc2c1OC
Reactant: N
Solvent: C1CCOC1
Product: COc1c(Cl)cc2c(N)nc(Cl)nc2c1OC
Yield: 81 %

Procedure:
Ammonia was passed into a solution of 2,4,6-trichloro-7,8-dimethoxyquinazoline (31.4 g., 0.107 mole) in 650 ml. dry tetrahydrofuran for one hour at room temperature. After stirring for an additional hour, the suspension was concentrated in vacuo and filtered. The solid was resuspended in water, filtered, washed with water and methanol. Recrystallization from dimethylformamide/water yielded 23.7 g. (81%) of the desired product, M.P., 360° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH2:12]([N:16]1[C:24]2[N:23]=[C:22]([Cl:25])[NH:21][C:20]=2[C:19](=[O:26])[N:18]([CH2:27][CH2:28][CH2:29][CH2:30]/[C:31](=[N:34]/[H])/[NH:32]O)[C:17]1=[O:36])[CH2:13][CH2:14][CH3:15]>CS(C)=O>[CH2:12]([N:16]1[C:24]2[N:23]=[C:22]([Cl:25])[NH:21][C:20]=2[C:19](=[O:26])[N:18]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[N:32]=[C:4]([C:3]3[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[O:6][N:34]=2)[C:17]1=[O:36])[CH2:13][CH2:14][CH3:15]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCCc2noc(-c3c(F)cccc3Cl)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 5.2 %

Procedure:
2-Chloro-6-fluorobenzoic acid (44 mg, 0.25 mmol) and CDl (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The mixture was purified by MDAP. The product fraction was combined and concentrated to give the title compound as a white solid (6.4 mg, 5%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1cccc(OCc2nc(-c3ccco3)oc2C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1cccc(COc2nn(Cc3ccccc3)cc2CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a solution of ethyl 1-benzyl-3-[(3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (1.0 g) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.07 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (0.61 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give {1-benzyl-3-[(3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazol-4-yl}methanol as a colorless oil (0.81 g, yield 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH2:20]([NH2:23])[CH2:21][CH3:22]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: CCCN
Product: CCCNc1c(C(=O)OCC)cnc2c(N)cccc12
Yield: 87 %

Procedure:
The compound prepared in Example 3 was reacted with propyl amine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 87%).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH3:9].C(N(CC)CC)C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C1COCC1.[Cu](I)I>[CH3:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cnccc1Br
Agent: I[Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cnccc1C#C[Si](C)(C)C
Temperature: 50 °C
Yield: 86.9 %

Procedure:
To a solution of 4-bromo-3-methyl pyridine hydrochloride (5.0 g, 24.0 mmol) in THF (degassed, 80 mL) was added copper iodide (450 mg, 2.40 mmol) and triethylamine (20.0 mL, 143.9 mmol). After degassing for 15 min, palladium tetrakis triphenylphosphine (830 mg, 0.72 mmol) and trimethylsilylacetylene (6.10 mL, 43.16 mmol) were added. The mixture was heated at 50° C. for 16 h then cooled to rt and filtered. The crude residue was purified via silica gel chromatography (EtOAc-Hexanes, 10%) to afford the title compound (3.95 g, 87%) as clear but dark oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].O>C(Cl)Cl>[CH:15]([Si:18]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Br:1])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]
Reactant: OCc1ccccc1Br
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)[Si](OCc1ccccc1Br)(C(C)C)C(C)C
Reaction time: 1 h

Procedure:
To a solution of o-bromobenzyl alcohol (2.55 g, 13.6 mmol) and imidazole (1.36 g, 20 mmol) in CH2Cl2 (20 ml) was added triisopropylsilyl chloride (2.6 ml, 12 mmol) at RT. The obtained mixture was stirred at the same temperature for 1 h and then taken up to H2O. After phase separation, the aqueous phase was extracted twice with petroleum ether. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by filtration through a short column of silica gel to give the title compound as a colorless liquid.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:8]12[CH:23]([O:24]CC3C=CC4C(=CC=CC=4)C=3)[CH:12]([CH:13]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]3=[O:22])[O:14]1)[O:11][N:10]([CH3:36])[CH2:9]2)([CH3:4])([CH3:3])[CH3:2].O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:8]12[CH:23]([OH:24])[CH:12]([CH:13]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]3=[O:22])[O:14]1)[O:11][N:10]([CH3:36])[CH2:9]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CC2(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)OC(n3ccc(=O)[nH]c3=O)C(O1)C2OCc1ccc2ccccc2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CN1CC2(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)OC(n3ccc(=O)[nH]c3=O)C(O1)C2O
Reaction time: 0.08 h

Procedure:
To a solution of compound 53 (1 mmol) in anhydrous CH2Cl2 (10 mL) was added water (0.8 mL) and the biphasic solution was stirred for 5 minutes. To this solution is added DDQ (2.2 mmol). The reaction mixture was stirred for 8 hours when the reaction was complete. It was diluted with CH2Cl2 (100 mL) and washed with 2% sodium bisufite solution. The aqueous layer was extracted until all the compound was in organic layer. The organic layer was washed with saturated bicarbonate followed by brine then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified on silica gel to give compound 54 in nearly quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)CCC.C([O-])(=O)C.[NH4+:40]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:40]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(F)c(C(F)(F)F)c2)CC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Temperature: 160 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of 4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (29.4 g; 1.00 equiv; 67.99 mmol) in 1-butanol (150 mL; 1.64 mol), add ammonium acetate (15 equiv; 1.02 mol; 78.61 g) followed by TEA (1 equiv; 67.99 mmol; 9.48 mL). Stir the mixture at 160° C. in a sealed tube. After 3 h, cool to RT and partition between EA and water and wash the organic layer with water and brine. Concentrate in vacuo. Triturate the residue in MTBE, filter and dry in vacuo to give the title compound (18.23 g; 44.10 mmol; 64.86%) as a white solid. 1H NMR (300 MHz, DMSO): 12.01 (s, 1H), 8.08-8.04 (m, 2H), 7.70 (d, J=1.4 Hz, 1H), 7.49-7.43 (m, 1H), 3.99 (d, J=12.6 Hz, 2H), 2.92-2.85 (m, 3H), 1.91-1.87 (m, 2H), 1.64-1.51 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH2:19]([N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22](Cl)=[O:23])[CH3:20]>C(OCC)(=O)C.CCCCCCC>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][C:22](=[O:23])[N:21]([CH2:19][CH3:20])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CCN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(4-trifluoromethyl-phenoxy)-phenol and N-ethyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (ethyl acetate/heptane, 1:5) (77%, white crystals. HPLC-MS m/z=402.1 (M+1), Rt: 5.6 min.
Reaction SMILES: CC(C)=O.[O:5]1CCO[CH:6]1[CH2:10][C:11]1([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CCOCC>[CH3:29][N:21]([CH2:20][C:11]1([CH2:10][CH:6]=[O:5])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26]
Reactant: CN(CC1(CC2OCCO2)CCc2ccccc21)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: CN(CC1(CC=O)CCc2ccccc21)C(=O)OC(C)(C)C
Yield: 55.5 %

Procedure:
An acetone solution of tert-butyl [1-(1,3-dioxolan-2-ylmethyl)-2,3-dihydro-1H-inden-1-yl]methyl(methyl)carbamate (14.33 g, 41.24 mmole), para-toluene sulfonic acid (1 equivalent) and 50 ml of water were stirred overnight at room temperature. Evaporation of the acetone resulted in an oily slurry. Ether was added and washed with water, followed by NaHCO3 sat. and dried over MgSO4. Evaporation of the ether followed by flash chromatography on silica with 15% EtOAc and hexanes afforded 6.9383 g of tert-butyl methyl{[1-(2-oxoethyl)-2,3-dihydro-1H-inden-1-yl]methyl}carbamate as an oil.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[N+:8]([C:11]1[CH:21]=[CH:20][C:14]([CH2:15][O:16][C:17](Cl)=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].C(N(CC)CC)C>C(Cl)Cl>[OH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:17]([O:16][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:21][CH:20]=2)=[O:18])[CH2:4]1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: O[C@@H]1CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
To a suspension of (3R)-3-hydroxypyrrolidine hydrochloride (7.00 g, 56.6 mmol) in methylene chloride (210 ml) were added chloroformic acid p-nitrobenzyl ester (13.4 g, 62.3 mmol) and triethylamine (17.4 ml, 125 mmol) in an ice bath. The mixture was stirred at room temperature for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1)→ethyl acetate as the eluant to afford (3R)-3-hydroxy-1-(p-nitrobenzyloxycarbonyl)-pyrrolidine (13.6 g, yield 90%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[CH:9]=2)=[N:6][CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:19][N:17]1[CH:18]=[C:14]([C:10]2[CH:9]=[C:8]([C:5]3[N:4]=[CH:3][C:2]([C:36]4[CH:35]=[N:34][N:33]([CH:30]5[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]5)[CH:37]=4)=[CH:7][N:6]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=[N:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cn1cc(-c2cccc(-c3ncc(Br)cn3)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cn3)c2)cn1
Temperature: 100 °C
Yield: 94.7 %

Procedure:
A solution of 5-bromo-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2, 160 mg, 0.50 mmol), 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Combi-blocks, 287 mg, 0.76 mmol) and Na2CO3 (140 mg, 0.12 mmol) in dry Toluene: Ethanol (1:1) (5 mL) was purged with nitrogen for 30 min before the addition of Pd(PPh3)4 (60 mg, 0.05 mmol). The reaction mixture was then heated at 100° C. O/N and filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the crude product. Purification by Flash chromatography on silica (hexane:EtOAc) afforded the title compound as a yellow solid (230 mg, 93%). 1H NMR (400 MHz, DMSO-d6): δ 9.15 (s, 2H), 8.53 (d, J=8.0 Hz, 2H), 8.25 (s, 1H), 8.21 (d, J=7.76 Hz, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.91-7.48 (m, 10H), 4.45-4.44 (m, 1H), 4.07-4.04 (m, 2H), 3.88 (s, 3H), 2.12 (s, 2H), 2.70 (d, J=3.44 Hz, 1H), 2.08-2.05 (m, 2H), 1.86-1.76 (m, 2H), 1.42 (s, 9H). HPLC (Condition A): Rt 4.68 min (purity 87%). MS (ESI+): 486.2.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=1[Cl:15])(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([C:33]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=2)[CH:11]=[CH:10][C:9]=1[Cl:15])(=[O:3])[CH3:2]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)ccc1Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2ccnc(C)c2)ccc1Cl

Procedure:
By carrying out the operation analogously to example 3, starting from 5-bromo-2-chlorophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 2-methyl-4-pyridineboronic acid, the expected product is obtained and is reacted further without additional purification in order to obtain the nonacetylated xyloside.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH3:6])[CH2:3][OH:4].[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>O1CCCC1>[OH:4][CH2:3][CH:2]([NH:1][C:10](=[O:11])[CH2:9][C:8](=[O:12])[CH3:7])[CH2:5][CH3:6]
Reactant: CCC(N)CO
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CCC(CO)NC(=O)CC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
34 ml (0.36 mol) of 2-amino-1-butanol were added dropwise to a solution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 46.97 g (0.27 mol, 76% yield) of a colorless oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([CH:7]([NH:12][C:13]([CH:15]([C:20](=[CH2:24])[C:21]([OH:23])=[O:22])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][CH2:2]1.[SH:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1.C(OCC)C>CO>[CH:1]1([NH:4][C:5]([CH:7]([NH:12][C:13]([CH:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:20]([CH2:24][S:25][C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[C:21]([OH:23])=[O:22])=[O:14])[C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6])[CH2:3][CH2:2]1
Reactant: Sc1cccs1
Reactant: C=C(C(=O)O)C(CC(C)C)C(=O)NC(C(=O)NC1CC1)C(C)(C)C
Solvent: CCOCC
Solvent: CO
Product: CC(C)CC(C(=O)NC(C(=O)NC1CC1)C(C)(C)C)C(CSc1cccs1)C(=O)O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2-[1-(1 -Cyclopropylcarbamoyl-2,2-dimethyl-propylcarbamoyl)-3-methyl-butyl]-acrylic acid (4.40 g, 12.4 mmol) was dissolved in methanol (10 ml) and placed under a blanket of argon prior to addition of 2-mercaptothiophene (4.5 ml). The mixture was stirred overnight at 60° C. under argon with the exclusion of light. The solvent was removed under reduced pressure to leave an oil to which was added cold diethyl ether (200 ml). The product precipitated on standing in an ice bath and was removed by filtration and washing with thoroughly with cold diethyl ether. The product was further purified by trituration with hot ethyl acetate and column chromatography (silica gel, gradient elution, 0-20% methanol in dichloromethane). Fractions were combined and evaporated to yield the title compound as an pale yellow solid (6.95 g, including minor impurities). 1H-NMR (CDCl3, partial deuterium exchange); δ 8.10 (1H, m), 7.85 (1H, d, J=9.2 Hz), 7.35 (1H, m), 7.03 (1H, m), 6.88 (1H, m), 4.06 (1H, d, J=9.2 Hz), 2.85 (1H, m), 2.67 (2H, m), 2.51 (1H, m), 1.53 (1H, m), 1.25 (1H, m), 1.02 (1H, m), 0.87 (9H, s), 0.76 (3H, d, J=6.4 Hz), 0.71 (3 H, d,J=6.5 Hz), 0.61 (2H, m) and 0.32 (2H, m).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH3:37])[CH:25]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Reactant: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
To a solution of N-butyl-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (73 mg, 0.25 mmol) in anhydrous acetonitrile (5 mL) was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (75 mg, 0.25 mmol) and N,N-diisopropylethylamine (43 μL, 0.25 mmol). The resulting solution was heated at reflux under nitrogen for 2 h and then cooled to room temperature. The solvent was removed in vacuo and the residue diluted with water (10 mL) and extracted with CH2Cl2 (30 mL). The organic extract was separated by hydrophobic frit and the solvent removed in vacuo. Purification by SPE (Silica, 5 g) eluting 99:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (105 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH:12]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[OH:17][C:14]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13]1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccccc2)C1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccccc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
Benzyl-4-oxo-2-phenylpiperidine-1-carboxylate (1.64 g, 5.30 mmol) in THF (27 ml) was cooled to −78° C. and phenylmagnesium bromide (6.36 ml, 6.36 mmol) was added. The ice bath was removed and the solution stirred at room temperature for 2 h. Concentrate, dilute with EtOAc and wash twice with water. The organics were dried over MgSO4, concentrated, and purified on silica gel eluted using 30% EtOAc to afford 1.02 g of benzyl 4-hydroxy-2,4-diphenylpiperidine-1-carboxylate.