Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[NH:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][N:10]2[C:20](=[O:29])[C:21]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[N:22][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([B:38]2[O:42][C:41]([CH3:44])([CH3:43])[C:40]([CH3:46])([CH3:45])[O:39]2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([C:8]1[C:9]2[N:10]([C:20](=[O:29])[C:21]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([B:38]4[O:39][C:40]([CH3:46])([CH3:45])[C:41]([CH3:44])([CH3:43])[O:42]4)=[CH:36][CH:37]=3)[N:22]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(Cc2ccco2)nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn1-2
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC1(C)OB(c2ccc(CC3(Cc4ccco4)N=C4C(Cc5ccccc5)=NC(c5ccccc5)=CN4C3=O)cc2)OC1(C)C
Temperature: 25 °C

Procedure:
To a solution of 8-benzyl-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one, 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, potassium carbonate and potassium iodide (33 mg, 0.20 mmol) is added. The reaction mixture is stirred at room temperature and is heated to 40° C. until HPLC shows the completion of the reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[CH:23]=O)([CH3:7])[CH3:6])[CH3:2].C(OC1C=CC(C=O)=C(O)C=1)C1C=CC=CC=1.C(CC(Br)(C)C([O-])=O)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C:5]([O:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH3:23])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(OCc2ccccc2)ccc1C=O
Agent: [Pd]
Agent: CCCC(C)(Br)C(=O)[O-]
Agent: O=Cc1ccc(OCc2ccccc2)cc1O
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cc(O)ccc1C
Yield: 94.9 %

Procedure:
5.10 g (14.9 mmol) 2-(5-benzyloxy-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 4-benzyloxy-2-hydroxybenzaldehyde and ethyl-bromoisobutyrate in analogy to the procedure described in example 52A]) was dissolved in 100 ml of ethanol and hydrogenated with 1.0 g of Pd—C (5%), 2 bar H2, 25° C., for two hours. The reaction mixture was filtered (Celite), the filter cake was washed twice with EtOH and the filtrate was evaporated. The crude product was purified by flash chromatography (SiO2, heptane/EtOAc) to give 3.37 g of the title compound as light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH2:12][O:13][CH3:14].O1CCCC1.C(OP([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(OCC)=O)C.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:5][C:4]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: COCOc1cc(C=O)ccc1OC
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(OC)c(OCOC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 4.2 %

Procedure:
The compound (3.42 g, 17.4 mmol) of Example 9-1 was dissolved in N,N-dimethylformamide (30 ml) and tetrahydrofuran (30 ml) and then thereto were added ethyl diethylphosphonoacetate (3.91 g, 17.4 mmol) and sodium hydride (766 mg, 19.1 mmol). After stirring for 2 hours at 60° C., the mixture was allowed to cool to room temperature, and tetrahydrofuran was removed under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate-toluene (3:1). The organic layer was washed with water and an aqueous saturated sodium chloride solution in the order, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the subject compound (196 mg, 88.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][C:21]=1[C:10]([CH:9]([CH3:13])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:12]
Reactant: COc1cccc(OC)c1
Reactant: COc1ccc(C(C)C(=O)O)cc1
Product: COc1ccc(C(C)C(=O)c2ccc(OC)cc2OC)cc1
Temperature: 75 °C
Reaction time: 5 h
Yield: 56.6 %

Procedure:
2-(p-Methoxyphenyl)propionic acid (0.39 g, 4 mmol) and 1,3-dimethoxybenzene (0.5 g, 0.5 ml, 4 mmol) were mixed in polyphosphoric acid (PPA) (10 g) and the reaction mixture was mechanically stirred at 75° C. for 5 h. The reaction mixture was then allowed to cool to room temperature and mechanically stirred for a further 12 h. The reaction was then quenched with ice water and the product extracted with CHCl3(3×25 ml). The CHCl3 layer was dried (Na2SO4) and the solvent removed under reduced pressure The residual crude product was purified by silica gel column chromatography (eluent 7:2 CH2Cl2:EtOAc) to give the pure 2,4,4′-trimethoxy-α-methyldesoxybenzoin (0.68 g, 58%)
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([CH:9]([CH2:15][C:16]([OH:18])=O)[C@@H:10]([C:12]([OH:14])=O)N)[CH3:8].[CH2:19]1COCC1>>[CH2:7]([CH:9]([CH2:15][CH2:16][OH:18])[CH:10]([CH3:19])[CH2:12][OH:14])[CH3:8]
Reactant: C1CCOC1
Reactant: CCC(CC(=O)O)[C@H](N)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC(CCO)C(C)CO
Temperature: 36 °C
Reaction time: 6 h

Procedure:
To a slurry of LAH (2.06 g, 54.29 mmol) in THF (60 mL) was added 3-ethylglutamic acid (3.5 g, 21.71 mmol) dropwise at 0° C. over 20 min. The reaction was heated to 36° C. for 18 h. The reaction slurry (gray) was cooled to 0° C. and quenched with H2O (3 mL) then washed with 1N NaOH (9 mL) and H2O (3 mL), It was then stirred for 6 h at 25° C. to obtain an off-white slurry. The slurry was filtered and the mother liquor was further dried over MgSO4, filtered and concentrated in vacuo to obtain 3-ethyl-2-methylpentane-1,5-diol as a crude yellow oil (2.85 g, 89.17%). Mass Spectrum (+ESI): 170 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19](/[CH:20]=[C:21]2/[C:22](=[O:27])[NH:23][C:24](=[O:26])[S:25]/2)=[CH:18][CH:17]=1>C(#N)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19](/[CH:20]=[C:21]2\[C:22](=[O:27])[NH:23][C:24](=[O:26])[S:25]\2)=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Solvent: CC#N
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(/C=C2/SC(=O)NC2=O)cc1
Yield: 20 %

Procedure:
A solution of (Z)-5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylidene}-2,4-thiazolidinedione (200 mg) in acetonitrile (750 ml), in a quartz tube under a stream of nitrogen, was irradiated by a 300 W high-pressure mercury lamp for 3 hours. The solvent was distilled off, and the resulting crystals were chromatographed on a column of silica gel (200 g). Elution with hexane-ethyl acetate (1:1, V/V) gave (E)-5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylidene}-2,4-thiazolidinedione (40 mg, 20.0%). Recrystallization from dichloromethaneethanol yielded colorless needles, m.p. 216°-217° C. Elemental analysis for C22H18N2O4S; Calcd.: C, 65.01; H, 4.46; N, 6.89. Found: C, 64.69; H, 4.26; N, 7.11. The subsequent elution with hexane-ethyl acetate (1:1, V/v) allowed the recovery of (Z)-5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylidene}-2,4-thiazolidinedione (138 mg, 69.0%).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([N+:23]([O-])=O)=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.Cl>CCO.CCOC(C)=O.[Fe]>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1
Reactant: C[C@@H](Oc1c([N+](=O)[O-])ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 3-bromo-7-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-nitrofuro[3,2-c]pyridine (1.00 g, 2.22 mmol) in EtOH (10 mL) was added iron (0.62 g, 11.1 mmol), followed by 0.1 N aq. HCl (1.1 mL, 0.11 mmol) at 95° C. (bath temp). The resulting mixture was stirred at this temperature for 30 min. Additional 0.1 N aq. HCl (1.1 mL, 0.11 mmol) was added and the mixture was refluxed for another 30 min. TLC and LC-MS showed the reaction was complete. The mixture was diluted with EtOAc (100 mL) and the solid was filtered off through a pad of Celite. The mother liquor was washed with brine (3×25 mL) and dried over anhydrous sodium sulfate. Evaporation of solvents under reduced pressure afforded the title compound as a light-yellow semi-solid (930 mg, 100% yield). 1H NMR (CDCl3, 400 MHz): δ=1.87 (d, J=6.6 Hz, 3H), 5.15 (br s, 2H), 6.55 (q, J=6.6 Hz, 1H), 7.06 (dd, J=9.1, 8.1 Hz, 1H), 7.27 (dd, J=9.1, 5.1 Hz, 1H), 7.44 (s, 1H), 7.96 (s, 1H). MS (ES+): 418.91/420.86/422.89 [MH+].
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH2:7][CH2:8][NH:9][C:10]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13])([CH3:4])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:41]=[CH:40][C:25]([O:26]C2C=CC(C#N)=C(OCC(F)F)N=2)=[CH:24][C:23]=1[CH:42]=[O:43].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:16]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([NH:9][CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:20])[CH3:19])[N:17]=2)=[CH:24][C:23]=1[CH:42]=[O:43]
Reactant: CC(C)(C)[Si](C)(C)OCCNc1nc(Cl)ccc1C#N
Reactant: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)nc1OCC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCNc1nc(Oc2ccc(Br)c(C=O)c2)ccc1C#N
Temperature: 80 °C
Yield: 75.6 %

Procedure:
To a solution of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-6-chloro-nicotinonitrile (4, 1.1 g, 3.5 mmol) in DMF (80 mL) were added 2-bromo-5-hydroxy-benzaldehyde (5, 0.75 g, 3.7 mmol) and K2CO3 (0.97 g, 7.05 mmol). The reaction was heated at 80° C. for 24 h. The DMF was removed in vacuo. Purification was accomplished by Biotage silica gel chromatography with 1%-3% EtOAc/hexanes gradient to afford 1.26 g (75% yield) of the title compound.
Reaction SMILES: CC1C=CC(S(Cl)(=O)=O)=CC=1.[CH2:12]([OH:18])[CH2:13][C:14]#[C:15][CH2:16][CH3:17].N1C=CC=CC=1.CC1C=CC(S(OCCC#CCC)(=O)=O)=CC=1.[O:42]=[CH:43][C:44]1[CH:52]=[CH:51][C:49](O)=[C:46]([O:47][CH3:48])[CH:45]=1>C(Cl)Cl>[CH2:12]([O:18][C:49]1[CH:51]=[CH:52][C:44]([CH:43]=[O:42])=[CH:45][C:46]=1[O:47][CH3:48])[CH2:13][C:14]#[C:15][CH2:16][CH3:17]
Reactant: CCC#CCCO
Reactant: COc1cc(C=O)ccc1O
Agent: CCC#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC#CCCOc1ccc(C=O)cc1OC
Yield: 38.7 %

Procedure:
4-Methylbenzenesulfonyl chloride (5.7 g, 30 mmol), 3-hexyn-1-ol (1.5 mL, 20 mmol) and pyridine (3.2 mL, 40 mmol) in CH2Cl2 (20 mL) were treated according to Procedure 4 giving hex-3-ynyl 4-methylbenzenesulfonate (3.8 g, 75%) as a colourless oil. Vanillin (0.76 g, 5.0 mmol) was alkylated with hex-3-ynyl 4-methylbenzenesulfonate (1.9 g, 7.5 mmol) according to Procedure 4 and the crude product was recrystallised from EtOAc/petrol to provide 4-(hex-3-ynyloxy)-3-methoxybenzaldehyde (0.45 g, 39%) as a colourless crystalline solid; mp 80-81° C.; δH (400 MHz, CDCl3) 1.12 (t, J=7.6 Hz, 3H, CH3), 2.17 (tq, J=7.6, 2.4 Hz, 2H, CH3CH2), 2.73 (tt, J=7.6, 2.4 Hz, 2H, OCH2CH2C), 3.92 (s, 3H, OCH3), 4.19 (t, J=7.6 Hz, 2H, OCH2), 7.00 (d, J5,6=8.0 Hz, 1H, H5), 7.41 (d, J2,6=1.6 Hz, 1H, H2), 7.44 (dd, J5,6=8.0, J2,6=1.6 Hz, 1H, H6), 9.85 (s, 1H, CHO); δC (100 MHz, CDCl3) 12.4, 14.0, 19.5, 56.0, 67.6, 74.3, 84.0, 109.5, 111.8, 126.6, 130.3, 149.9, 153.5, 190.8; vmax 1023, 1134, 1263, 1586, 1680, 2877, 2972 cm−1.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[N:13]=[C:12]([N:14]2[C:18]3=[CH:19][N:20]=[C:21]([C:23]4[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:30])[CH:22]=[C:17]3[C:16]([CH:31]([OH:37])[CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:15]2)[CH:11]=[C:10]([CH2:38][CH3:39])[N:9]=1>CO>[CH3:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]=1[C:21]1[CH:22]=[C:17]2[C:16]([CH:31]([OH:37])[CH:32]([CH2:33][CH3:34])[CH2:35][CH3:36])=[CH:15][N:14]([C:12]3[CH:11]=[C:10]([CH2:38][CH3:39])[N:9]=[C:8]([O:4][CH3:1])[N:13]=3)[C:18]2=[CH:19][N:20]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(-n2cc(C(O)C(CC)CC)c3cc(-c4c(C)cccc4C)ncc32)nc(Cl)n1
Agent: [Cs+]
Solvent: CO
Product: CCc1cc(-n2cc(C(O)C(CC)CC)c3cc(-c4c(C)cccc4C)ncc32)nc(OC)n1
Temperature: 60 °C

Procedure:
Cs2CO3 (85 mg, 0.26 mmol) is added to a solution of 1-[1-(2-chloro-6-ethyl-pyrimidin-4-yl)-5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-ol (100 mg, 0.22 mmol) in MeOH (4 mL). The mixture is heated at 60° C. for 30 min. The mixture is concentrated under reduced pressure, diluted with water (5 mL), and the product is extracted with DCM. The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated under reduced pressure. Chromatography of the residue silica gel (hexane-EtOAc, 1:1) gives 1-[5-(2,6-dimethyl-phenyl)-1-(6-ethyl-2-methoxy-pyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-ol as colorless oil: 1H NMR (CDCl3) 10.18 (s, 1H), 8.39 (s, 1H), 7.54 (s, 1H), 7.27-7.12 (m, 3H), 6.41 (s, 1H), 5.00 (d, J=6 Hz, 1H), 4.12 (s, 3H), 2.78 (dd, J=7, 15 Hz, 2H), 2.075 (s, 6H), 1.39 (t, J=7 Hz), 2.05-1.26 (m, 5H), 0.92 (t, J=7 Hz, 6H); LCMS (1) m/z 459.33 (2.65 min).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@:10]4([OH:21])[C@:15]3([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:22]>CS(C)=O>[OH:21][C@:10]12[CH2:11][C:12](=[O:20])[CH2:13][CH2:14][C@:15]1([CH3:16])[C@@H:17]1[C@H:7]([C@H:6]3[C@@:2]([CH2:19][CH2:18]1)([CH3:1])[C:3](=[O:22])[CH2:4][CH2:5]3)[CH2:8][CH2:9]2
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@@]4(O)C[C@@H](O)CC[C@]34C)[C@@H]1CC[C@@H]2O
Solvent: CS(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CC[C@@]4(O)CC(=O)CC[C@]34C)[C@@H]1CCC2=O
Reaction time: 0.25 h

Procedure:
A solution of androstane-3β,5α,17β-triol (0.48 g) and IBX (0.72 g) in DMSO (8 mL) was stirred at −15° C. overnight and then quenched at room temperature by addition of H2O (40 mL). After stirring for 15 min, the mixture was filtered and the cake was washed with EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc (3×40 mL). The combined organic extracts were dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/CH2Cl2/acetone 60/20/20) to give the title compound II-aa (0.36 g, 75%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.48 (1H, s), 2.72 (1H, d), 2.60-1.18 (20H, m), 1.23 (3H, s), 0.86 (3H, s).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH:8]1([CH3:18])[CH2:13][CH2:12][CH:11]([CH:14]([CH3:16])[CH3:15])[CH:10](O)[CH2:9]1.S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[C:1]([O:7][CH:10]1[CH:11]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:13][CH:8]([CH3:18])[CH2:9]1)(=[O:6])[CH2:2][C:3]([O:5][CH:10]1[CH:11]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:13][CH:8]([CH3:18])[CH2:9]1)=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CCC(C(C)C)C(OC(=O)CC(=O)OC2CC(C)CCC2C(C)C)C1
Yield: 76.2 %

Procedure:
Malonic acid (22.2 g, 0.213 mol) and menthol (70 g, 0.448 mol) are brought to reflux for 6 hours in 100 ml of toluene in the presence of 2 ml of concentrated sulfuric acid in a reactor surmounted by a Dean & Stark apparatus. The water formed is removed by azeotropic distillation. The organic phase is washed 3 times with water and is dried over sodium sulfate. The excess menthol is removed by distillation under vacuum (140° C. under 0.6 hPa). The residue is treated with animal charcoal in isopropanol at reflux. After filtering, rinsing and evaporating the solvent, 61.8 g (Yield 76%) of dimenthyl malonate are obtained in the form of a yellow oil which is used as is in the following stage.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.CCN(CC)CC>C(Cl)Cl.CCOCC>[CH:12]([C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C=O)C1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of DMSO (0.73 mL, 10.2 mmol) in CH2Cl2 (30 mL) at −78° C. was added a solution of oxalyl chloride (0.45 mL. 5.1 mmol) in CH2Cl2 (30 mL). The reaction mixture was stirred for 10 min at −78° C. prior to the addition of a solution of (R)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate in CH2Cl2 (5 mL). The mixture was stirred for an additional 30 min at −78° C. Et3N (3.2 mL, 23.2 mmol) was then added in one portion and the mixture was stirred for 10 min at −78° C. and another 30 min while warming to rt. The solution is poured in Et2O (50 mL) and Brine (50 mL), separated. The aqueous phase was extracted with Et2O (2×50 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to afford (R)-tert-butyl 3-formylpiperidine-1-carboxylate which was used in the next step without purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]=[CH:3]1.[Cl:9]N1C(=O)CCC1=O>O1CCOCC1>[Cl:9][C:5]1[N:4]=[CH:3][N:2]([CH3:1])[C:6]=1[CH2:7][OH:8]
Reactant: Cn1cncc1CO
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1COCCO1
Product: Cn1cnc(Cl)c1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of (1-methyl-1H-imidazol-5-yl)methanol (1.14 g, 10 mmol) in dioxane (50 mL), in a 250 mL round bottom flask, was added 1-chloropyrrolidine-2,5-dione (1.38 g, 10 mmol). The resulting mixture was stirred at room temperature overnight. Dioxane was removed under vacuum to provide (4-chloro-1-methyl-1H-imidazol-5-yl)methanol. The crude (4-chloro-1-methyl-1H-imidazol-5-yl)methanol was dissolved in 40 mL of chloroform, followed by addition of tribromophosphane (1.9 mL, 20 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was evaporated to provide 5-(bromomethyl)-4-chloro-1-methyl-1H-imidazole.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:42])[CH:11]([N:15]1[C@H:18]([S:19][S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[C@@H:17]([O:30][C:31](=[O:40])[CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:16]1=[O:41])[C:12](=[CH2:14])[CH3:13]>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:42])[C:11]([N:15]1[C@H:18]([S:19][S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[C@@H:17]([O:30][C:31](=[O:40])[CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:16]1=[O:41])=[C:12]([CH3:14])[CH3:13]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.4 ml of triethylamine is added to a solution of 1.28 g (2.41 mmole) of 2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-phenoxyacetoxy-2-oxoazetidin-1-yl]-3-methylenebutyric acid methyl ester in 30 ml of methylene chloride and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is diluted with 50 ml of methylene chloride, washed in succession with 2N hydrochloric acid, water and sodium chloride solution, dried over sodium sulphate and freed from solvent in vacuo. The residue is purified by chromatography over silica gel with toluene/ethyl acetate (19:1) and yields the title compound in the form of a faint yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:14]1[O:22][C:21]2[C:16](=[C:17]([CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:18]=[CH:19][CH:20]=2)[O:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[O:1]=[C:2]1[C:11]([CH2:12][N:28]2[CH2:29][CH2:30][CH:25]([CH2:24][CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[O:22][CH2:14][O:15][C:16]=34)[CH2:26][CH2:27]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=Cc1cc2ccccc2[nH]c1=O
Reactant: c1cc(CCC2CCNCC2)c2c(c1)OCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2cc1CN1CCC(CCc2cccc3c2OCO3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.9 %

Procedure:
In 50 ml of tetrahydrofuran were dissolved 0.24 g of 2-oxo-1,2-dihydro-3-quinolinecarboxaldehyde and 0.3 g of 4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine. To the mixture were added 0.5 ml of acetic acid and 0.42 g of sodium triacetoxyborohydride were added thereto, followed by stirring at room temperature for 12 hours. An aqueous saturated sodium bicarbonate aqueous solution was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting solid was collected by filtration, to give 130 mg of the title compound as a light brown solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=O)=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18][N:20]([CH3:21])[CH3:22])=[CH:2]1
Reactant: CN(C)C(=O)Cc1ccccc1Sc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCc1ccccc1Sc1c[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 16 h

Procedure:
2-[2-(1H-Indol-3-ylsulfanyl)-phenyl]-N,N-dimethyl-acetamide (116 mg, 0.37 mmol) in 6 mL THF is added to LiAlH4 (43 mg, 1.12 mmol) in 4 mL THF. The reaction mixture is stirred 16 hours at 50° C. The reaction is quenched with water and 2N NaOH. The reaction mixture is stirred for 1 hour, then 2.5 mL water is added and stirring was continued for another hour. The mixture is filtered, dried with MgSO4 and concentrated in vacuo. Purification by flash chromatography or preparative HPLC to gives the title compound. The following compounds were prepared analogously:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[C@@H:22]12[CH2:28][C@@H:25]([CH2:26][CH2:27]1)[CH2:24][NH:23]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C@@H:22]12[CH2:28][C@@H:25]([CH2:26][CH2:27]1)[CH2:24][N:23]2[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14]
Reactant: C1C[C@H]2C[C@@H]1CN2
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1C[C@@H]2CC[C@H]1C2

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (1S,4R)-2-azabicyclo[2.2.1]heptane hydrochloride (175275-72-6) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=364.5 [MH+].