Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>O.CN(C)C=O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][CH2:21][C:4]1([C:1](=[O:3])[CH3:2])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13])[CH3:27]
Reactant: CCOC(=O)CCBr
Reactant: CC(=O)C1Cc2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCC1(C(C)=O)Cc2ccccc2C1=O
Temperature: 52.5 °C
Reaction time: 0.33 h

Procedure:
2-Acetyl-1-indanone (15 g, cf. Liebigs Ann. Chem. 347 (1906) 112) was added into a mixture of potassium carbonate (8.5 g) and dry N,N-dimethylformamide (45 ml). The mixture was stirred at 50-55° C. for 20 minutes and ethyl 3-bromopropionate (19 g) was then added and the stirring was continued at 50-55° C. for 6 hours. Water (60 ml) was added to the reaction mixture and the pH of the solution was adjusted to 2-3 with hydrochloric acid. The mixture was stirred at 50-55° C. for one hour. The cooled solution was extracted with toluene, washed with water, dried with sodium sulfate, and the solvent removed under reduced pressure. The yield was 23.5 g.
Reaction SMILES: [BrH:1].[CH2:2]([NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[C:12]=2[NH2:16])[CH2:7]1)[CH2:3][CH3:4].[CH:18](O)=[O:19].C(OC(=O)C)(=O)C>C(OCC)C>[BrH:1].[CH2:2]([NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[C:12]=2[NH:16][CH:18]=[O:19])[CH2:7]1)[CH2:3][CH3:4]
Reactant: O=CO
Reactant: CCCNC1CCc2c(ccc(O)c2N)C1
Agent: Br
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CCCNC1CCc2c(ccc(O)c2NC=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.9 g of 2-propylamino-5-amino-6-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide are introduced into a mixture of 6 ml of formic acid and 0.67 ml of acetic anhydride, kept in an ice-bath for 1/2 hour. The mixture is stirred for 3 hours at ambient temperature and then poured into diethyl ether. The precipitate which has formed is filtered off and washed with hot isopropyl alcohol. After drying, 1.7 g of the final compound are obtained, which melts at 210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([C:35]2[O:36][CH:37]=[CH:38][N:39]=2)=[C:30]([F:40])[CH:29]=1.ClC1C=CC(S(N(CC2C=CC(C3OC=CN=3)=C(F)C=2F)[C@@H]2CCCC[C@H]2CO)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:27][C:28]2[CH:29]=[C:30]([F:40])[C:31]([C:35]3[O:36][CH:37]=[CH:38][N:39]=3)=[CH:32][C:33]=2[F:34])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Fc1cc(-c2ncco2)c(F)cc1CBr
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1cc(F)c(-c2ncco2)cc1F)[C@@H]1CCCC[C@H]1CO
Yield: 30.9 %

Procedure:
The title compound was synthesized from 4-chloro-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (90 mg, 0.30 mmol), cesium carbonate (117 mg, 0.36 mmol), and 2-(4-(bromomethyl)-2,5-difluorophenyl)oxazole (99 mg, 0.36 mmol) according to the procedure described for 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 20) to give 4-chloro-N-(2,5-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (46 mg, 31%). 1H NMR (400 MHz, CDCl3) δ ppm 7.77 (s, 1H), 7.74 (d, J=8.56 Hz, 2H), 7.68 (dd, J=9.95, 5.67 Hz, 1H), 7.52 (dd, J=9.95, 5.67 Hz, 1H), 7.49 (d, J=8.56 Hz, 2H), 7.29 (s, 1H), 4.52 (d, J=16.00 Hz, 1H), 4.37 (d, J=16.00 Hz, 1H), 3.53-3.65 (m, 2H), 3.12 (d, J=11.08 Hz, 1H), 2.57 (d, J=1.01 Hz, 1H), 1.58-1.77 (m, 3H), 1.36-1.53 (m, 2H), 0.98-1.21 (m, 4H). Analytical HPLC R.T.=22.02 min. MS [M+H]+=497. HRMS [M+H]+ calc'd 497.1113, found 497.1100.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:23][C:24]([NH2:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:28]#[N:29].C(N)CN>CN1CCCC1=O>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:28]#[N:29])=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:23][C:24]([NH2:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1cnc(Nc2ccc(Br)cc2)cc1NCc1ccccc1
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Solvent: NCCN
Product: N#Cc1ccc(Nc2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1
Temperature: 180 °C
Reaction time: 3 h
Yield: 14.9 %

Procedure:
20 mg of 4-(benzylamino)-6-[(4-bromophenyl)amino]pyridine-3-carboxyamide (the compound of Example 54) was dissolved in 0.4 mL of 1-methyl-2-pyrrolidinone, to which 5 mg of copper cyanide (I) was added, and stirred at 180° C. for 3 hours. After cooling, a 30% aqueous solution of ethylenediamine was added to the reaction mixture, extracted with chloroform, the extract was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=10:1) to obtain 2.3 mg (13%) of the title compound as a light brown solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]1[N:26]=[C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=1.[F:35][C:36]([Si](C)(C)C)([F:38])[F:37].Cl>C1COCC1>[CH3:19][O:20][C:21]1[N:26]=[C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH:31]([OH:32])[C:36]([F:38])([F:37])[F:35])=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(-c2ccc(C=O)cc2)n1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(C(O)C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
Tetrabutylammonium fluoride (TBAF) (0.1 ml of 1M in THF) was added to a solution of 4-(6-methoxy-pyridine-2-yl)-benzaldehyde (213 mg, 1 mmol) and trifluoromethyl trimethylsilane (0.2 ml, 1.2 mmol) in 10 ml THF at 0° C. The mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was then treated with 12 ml of 1M HCl and stirred overnight. The product was extracted with ethyl acetate (3×20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 0.25g of 1-[4-(6-methoxy-pyridine-2-yl)-phenyl]-2,2,2-trifluoro-ethanol which was directly used in next step without purification. yield: 90%.
Reaction SMILES: [C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH3:17][O-:18].[Na+]>CO>[C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[O:18][CH2:17]2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(=O)NC=Cc1ccc(OC(C)=O)cc1
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC=Cc1ccc(OCC2CO2)cc1
Temperature: 50 °C

Procedure:
13.0 g (0.05 mol) of p-(2-acetylaminovinyl)-acetoxybenzene are suspended in 100 ml of absolute methanol, a solution of 2.8 g (0.05 mol) of sodium methoxide in 20 ml of absolute methanol is added and thereafter the mixture is warmed to 50° C. for 15 minutes. It is then evaporated to dryness in vacuo. The resulting crude phenolate of p-(2-acetylaminovinyl)-phenol is heated with 65 ml of epichlorohydrin to the boil for 18 hours, under a reflux condenser and whilst stirring. Thereafter, the excess epichlorohydrin is removed by vacuum distillation. The residue is partitioned between water and ethyl acetate and the organic phase is siphoned off, dried over sodium sulphate and evaporated. After crystallisation of the crude product, thus obtained, from acetone-ether, 1-[p-(2-acetylaminovinyl)-phenoxy]-2,3-epoxy-propane of melting point 135°-137° C. is obtained.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:10][CH2:9][CH2:8]2>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:10][CH2:9][CH2:8]2
Reactant: COc1ccc2c(c1)CCN=C2c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCNC2c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
Sodium borohydride (0.945 g, 24.96 mmol) was added in small portions to a solution of 6-methoxy-1-phenyl-3,4-dihydroisoquinoline (1.480 g, 6.24 mmol) in MeOH (50 ml) at 0° C. The reaction mixture was stirred for 30 min, warmed to rt and stirred at rt for 19 hr, then quenched by the dropwise addition of H2O (10 ml). Excess MeOH was removed by evaporation and the resulting aqueous solution was extracted with CHCl3 (4×10 ml). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give 1.308 g (88% yield) of white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]([CH2:23][CH:24]=[CH:25][CH3:26])[CH2:17][C:18](OCC)=[O:19])=[O:15])=[CH:9][CH:8]=1)[CH2:4][CH2:5][CH3:6].O(C)[Na]>CO>[CH2:23]([N:16]1[CH2:17][C:18](=[O:19])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([C:3](=[N:2][OH:1])[CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=2)[C:14]1=[O:15])[CH:24]=[CH:25][CH3:26]
Reactant: CC=CCN(CC(=O)OCC)C(=O)Nc1ccc(C(CCC)=NO)cc1
Agent: CO[Na]
Solvent: CO
Product: CC=CCN1CC(=O)N(c2ccc(C(CCC)=NO)cc2)C1=O

Procedure:
0.01 mol of this urea is dissolved in 150 mL of CH3OH. the pH is adjusted to approximately 10.0 using 25% NaOCH3 solution in CH3OH. The solution is heated to reflux for 2.5 hours, after which time the solvent is removed in vacuo. The residue is washed with cold water and dried in vacuo to yield crude 1-(2-butenyl)-3-[4-(1-hydroxyiminobutyl)phenyl]hydantoin. The hydantoin ispurified by recrystallization from CH3OH: H2O.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[CH:13]([Mg]Br)([CH3:15])[CH3:14]>C1COCC1>[F:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][CH:13]([CH3:15])[CH3:14])[C:7]=2[CH:8]=1
Reactant: CC(C)[Mg]Br
Reactant: Fc1ccc2scc(CBr)c2c1
Solvent: C1CCOC1
Product: CC(C)Cc1csc2ccc(F)cc12
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 3-bromomethyl-5-fluorobenzothiophene (2.0 g; cf. Raga, Manuel; Palacin, Celia; Castello, Josep Maria; Ortiz, Jose A.; Cuberes, Maria Rosa; Moreno-Manas, Marcial, Eur. J. Med. Chem. (1986), 21(4), 329-32) in THF (30 ml) was added over 5 minutes isopropylmagnesium bromide (1.0 M, 16.6 ml). The reaction mixture was stirred at 50° C. for 5 h, cooled, quenched with ice/water and ammonium chloride solution, and extracted with ethyl acetate. The organic phases were washed with water, dried and concentrated. The residue was chromatographed on silica gel using heptane/methylene chloride as eluent to obtain the title compound (1.35 g) as a yellowish oil. MS (EI): 208.3 (M)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[OH:43][C:26]([CH3:42])([CH3:25])[CH2:27][N:28]1[CH:32]=[C:31]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([N:15]5[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:16]5=[O:23])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:24]=2)[CH:30]=[N:29]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(N4C(=O)NC(=O)C4(C)C)nc2-3)cn1
Yield: 12 %

Procedure:
1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol under Suzuki conditions to give 485. Yield 12% MS (ESI+): 468.2. 1H NMR (400 MHz, DMSO) δ 11.86 (s, 1H), 8.16 (t, J=8.8, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.38 (dd, J=8.2, 1.8, 1H), 7.24 (d, J=1.8, 1H), 4.73 (s, 1H), 4.33 (t, J=4.9, 2H), 4.03 (s, 2H), 3.25 (t, J=5.0, 2H), 1.78 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(Br)C=C.CCOC(C)=O>C1(C)C=CC=CC=1>[CH2:3]([CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]1=[O:13])[CH:2]=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCCC1
Agent: [K+]
Solvent: C=CCBr
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCC1CCCCC1=O
Temperature: 0 °C
Yield: 71.6 %

Procedure:
EX-6a) A suspension of potassium t-butoxide (200 g, 1.78 mol) in toluene which was cooled to 0° C. in an ice bath under N2 was treated with cyclohexanone (157 g, 1.60 mol). To the reaction mixture was slowly added allyl bromide (194 g, 1.60 mol) over a 2 hour period. The reaction was warmed to room temperature over 5 hours. The reaction was then poured into EtOAc (400 mL) and washed once with 10% potassium hydrogen sulfate (250 mL). The organic solution was then washed with brine (3×200 mL), dried over magnesium sulfate, and evaporated under reduced pressure. The resulting oil was then chromatographed to yield 158.4 g (71.6%) of 2-allyl cyclohexanone as an oil.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:34].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[C:20]([OH:22])=[O:34])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc1OC
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1OC

Procedure:
In analogy with Example 44d), 778 mg of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(3,4-dimethoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 27.67 ml of dimethoxyethane and 13.91 ml of water are hydrolysed with 6.83 ml of 1M lithium hydroxide solution to give the title compound, which is subjected directly to further processing. TLC Rf (C)=0.07.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@@H:14]([N:16]([CH:24]=[O:25])[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH3:15])[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.Cl.[N:72]1[CH:77]=[CH:76][CH:75]=[C:74]([NH:78][C:79](=[O:86])[C@@H:80]([NH2:85])[C:81]([CH3:84])([CH3:83])[CH3:82])[CH:73]=1>CN(C=O)C>[CH3:82][C:81]([CH3:84])([CH3:83])[C@H:80]([NH:85][C:11](=[O:13])[C@H:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@@H:14]([N:16]([CH:24]=[O:25])[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[CH3:15])[C:79](=[O:86])[NH:78][C:74]1[CH:73]=[N:72][CH:77]=[CH:76][CH:75]=1
Reactant: CC(C)(C)[C@H](N)C(=O)Nc1cccnc1
Reactant: C[C@@H]([C@@H](CCCc1ccccc1)C(=O)O)N(C=O)OC1CCCCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@@H]([C@@H](CCCc1ccccc1)C(=O)N[C@H](C(=O)Nc1cccnc1)C(C)(C)C)N(C=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a solution of (2R,3S)-2-(3-phenyl-1-propyl)-3-(formyl-2-tetrahydropyrariyloxyamino)butanoic acid (120 mg, 0.344 mmol) in DMF (1 mL) is added BOP reagent (167 mg, 0.378 mmol), HOBt (51 mg, 0.378 mmol), and NMM (174 mg, 1.72 mmol). After 30 min, (2S)-2-amino-3,3-dimethylbutanoic acid 3-pyridylamide dihydrochloride (118 mg, 0.410) is added and the resulting solution is stirred at 25° C. for 18 h. The reaction mixture is concentrated, diluted with EtOAc (20 mL) and washed sequentially with 1 M aqueous sodium carbonate and saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 2:1 EtOAc-hexane) to provide (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(3-phenyl-1-propyl)butanoic acid [(1S)-2,2-dimethyl-1-(3-pyridylcarbamoyl)-1-propyl]amide as a solid (115 mg, 62% yield). ESI-MS m/z 529 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([O:9][CH3:10])([CH3:8])[C:4](OC)=[O:5].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCCC>[CH2:11]([NH:18][C:4](=[O:5])[C:3]([O:9][CH3:10])([O:2][CH3:1])[CH3:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)C(C)(OC)OC
Solvent: CCCCCC
Product: COC(C)(OC)C(=O)NCc1ccccc1
Temperature: 55 °C
Reaction time: 288 h

Procedure:
A mixture of methyl 2,2-dimethoxypropionate (2.33 g, 15.7 mmol) and benzylamine (1.68 g, 15.7 mmol) in a 20 mL screw-capped vial was stirred at 55° C. for 12 d. To the reaction mixture, which mostly solidified upon cooling to ambient temperature was added hexane (5 mL), and the mixture was sonicated and stirred vigorously. The solid was filtered off, washed with hexanes, and dried in vacuo to give the title compound as off-white solid. 1H NMR (400 MHz, CDCl3): δ=7.38-7.25 (m, 5H), 7.08 (brs, 1H), 4.49 (d, J=5.6 Hz, 2H), 3.25 (s, 6H), 1.52 (s, 3H). MS(ES+): m/z=246.07 (58) [MNa+], 224.11 (58) [MH+], 192.12 (100) [MH+-MeOH], 160.11 (33) [MH+-2 MeOH]. HPLC: tR=2.78 min (polar—5 min, ZQ3).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C@H:11]([CH2:29][C:30]1[N:31]=[CH:32][NH:33][CH:34]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[C:17]([CH3:28])[CH:16]=1)=[O:13].CN1CCOCC1>C1COCC1>[NH:33]1[CH:34]=[C:30]([CH2:29][C@@H:11]([NH:10][C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[C:12](=[O:13])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[O:22])=[C:17]([CH3:28])[CH:16]=2)[N:31]=[CH:32]1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: Cc1cc(NC(=O)[C@H](N)Cc2c[nH]cn2)ccc1C(=O)N1CCCC1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)[C@@H](Cc2c[nH]cn2)NC(=O)c2ccc(Br)s2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 10c from 5-bromo-thiophene-2-carboxylic acid and (R)-2-amino-3-(1H-imidazol-4-yl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-propionamide with PPA and NMM in THF.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[C:22]3[O:21][C:20]([F:24])([F:23])[O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][C:5]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[C:22]3[O:21][C:20]([F:24])([F:23])[O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][C:5]=1[N:25]1[CH2:30][CH2:29][N:28]([CH3:33])[CH2:27][CH2:26]1
Reactant: COc1ccc(NS(=O)(=O)c2cccc3c2OC(F)(F)O3)cc1N1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2cccc3c2OC(F)(F)O3)cc1N1CCN(C)CC1

Procedure:
285 mg of the product were obtained by reaction of 2,2-Difluoro-benzo[1,3]dioxole-4-sulfonic acid (4-methoxy-3-piperazin-1-yl-phenyl)-amide hydrochloride with formaldehyde, sodium triacetoxyborohydride and sodium sulphate in dichloromethane.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5](=O)[NH:4][CH2:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].O>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5](=[S:22])[NH:4][CH2:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CNC(=O)C(c2ccccc2)(c2ccccn2)C1
Solvent: O
Solvent: c1ccccc1
Product: CN1CNC(=S)C(c2ccccc2)(c2ccccn2)C1

Procedure:
To a solution of 1,2,3,6-tetrahydro-1-methyl-5-phenyl-5-(2-pyridyl)-4(5H)-pyrimidinone in benzene is added 0.16 equivalent of phosphorus pentasulfide. The reaction mixture is heated gently for 30 minutes then water is added and the layers are separated. The aqueous layer is extracted again with benzene and the organic layers are combined, washed with water, dried (MgSO4) and concentrated in vacuo to give 1,2,3,6-tetrahydro-1-methyl-5-phenyl-5-(2-pyridyl)-4(5H)-pyrimidinethione.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([C:19](O)=[O:20])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1([NH2:28])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([NH:28][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:20])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:17])([F:18])[F:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NN1CCOCC1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: O=C(NN1CCOCC1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 12c) and 4-morpholinamine (CAN 4319-49-7) as starting materials; LC-MS (UV peak area/ESI) 99.0%, 388.1849 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:3]1.[Br-].[CH2:14]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:15][CH3:16].CC(C)([O-])C.[K+]>C1COCC1>[CH:14](=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:3]1)[CH2:15][CH3:16]
Reactant: COC(=O)CC1CCC(=O)CC1
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC=C1CCC(CC(=O)OC)CC1
Temperature: -10 °C

Procedure:
64.4 g of methyl (4-oxocyclohexyl)acetate and 137.9 g of propyltriphenylphosphonium bromide were introduced into 500 ml of THF, and the mixture was cooled to -10° C. with stirring under nitrogen. A solution of 40.17 g of potassium tert-butoxide in 400 ml of THF was then added dropwise with stirring at the same temperature, and the mixture was then stirred at RT for a further 2 h. Conventional work-up gave methyl (4-propylidenecyclohexyl)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:9]=[C:10]([Sn](C)(C)C)[C:3]=12.[B-](F)(F)(F)[F:26].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:9]=[C:10]([F:26])[C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2cc([Sn](C)(C)C)c3c(Cl)ccnc32)cc1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(F)c3c(Cl)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
488 mg (1.03 mmol) of 4-chloro-1-[(4-methylphenyl)sulfonyl]-3-(trimethylstannyl)-1H-pyrrolo[2,3-b]pyridine are initially charged in 20 ml of anhydrous acetonitrile. 368 mg (1.03 mmol) of Selectfluor® are then added in one portion, and the mixture is allowed to stir at RT overnight. For work-up, the precipitate formed is filtered off with suction and the filtrate is concentrated. The residue is purified by preparative HPLC. The product is a solid.