Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[C@H:42]([CH3:47])[CH2:41]3)=[CH:36][N:35]=2)[C:30](=[O:48])[N:29]([CH3:49])[CH:28]=1)(=O)C.O[Li].O>CC(O)C.C1COCC1.O>[CH3:47][C@H:42]1[N:43]([CH3:46])[CH2:44][CH2:45][N:40]([C:37]2[CH:38]=[CH:39][C:34]([NH:33][C:31]3[C:30](=[O:48])[N:29]([CH3:49])[CH:28]=[C:27]([C:7]4[C:6]([CH2:5][OH:4])=[C:11]([N:12]5[CH2:24][CH2:23][N:15]6[C:16]7[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=7[CH:22]=[C:14]6[C:13]5=[O:25])[CH:10]=[C:9]([F:26])[CH:8]=4)[CH:32]=3)=[N:35][CH:36]=2)[CH2:41]1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)[C@H](C)C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)CCN1C
Temperature: 30 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
A mixture of 108f (250 mg, 0.375 mmol) and LiOH.H2O (98 mg, 2.0 mmol) in iPrOH/THF (1:1, 3 mL) and H2O (1 mL) was stirred at 30° C. for 2 h. The mixture was evaporated in vacuo and the residue was extracted with EtOAc (10 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 108 (62 mg, 26%) as a white solid. LCMS: [M+H]+ 626. 1H NMR (500 MHz, CDCl3) δ 8.53 (s, 1H), 7.89 (d, J=2.5, 1H), 7.76 (s, 1H), 7.45 (d, J=2, 1H), 7.26 (s, 1H), 7.14-7.16 (m, 1H), 6.92-6.94 (m, 1H), 6.86 (s, 1H), 6.79 (d, J=9, 1H), 4.52-4.54 (m, 1H), 4.30-4.32 (m, 2H), 4.14-1.16 (m, 3H), 3.90-3.91 (m, 1H), 3.69 (s, 3H), 3.34-3.35 (m, 2H), 2.91-2.92 (m, 2H), 2.60-2.38 (m, 10H), 1.83-1.85 (m, 2H), 1.78-1.79 (m, 2H), 1.17 (s, 3H)
Reaction SMILES: [OH:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:17]([CH:19]1[O:21][CH2:20]1)[Cl:18]>N1CCCCC1>[Cl:18][CH2:17][CH:19]([OH:21])[CH2:20][O:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ccccc2oc2c(O)cccc12
Reactant: ClCC1CO1
Solvent: C1CCNCC1
Product: O=c1c2ccccc2oc2c(OCC(O)CCl)cccc12
Yield: 38 %

Procedure:
A mixture of 4-hydroxy-9-oxoxanthene (1.1 g), epichlorohydrin (4 g) and piperidine (0.01 g) is heated on a boiling water-bath for 5 hours. Excess epichlorohydrin is then removed by distillation and the residue is dissolved in ethyl acetate (50 ml). The organic solution is washed with 2N NaOH (20 ml) and concentrated to dryness yielding 1-chloro-2-hydroxy-3-(9-oxoxanth-4-yloxy)propane (0.6 g) as a raw product. A solution of this product in absolute ethanol (20 ml) is then added to a solution of 2-aminotetralin (0.3 g) in ethanol (10 ml) and the mixture is refluxed for 4 hours and then evaporated to dryness. The obtained residue is taken up in hydrogen chloride saturated-isopropanol affording the desired N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy -3-oxoxanth-4-yloxypropanamine hydrochloride ((i): R=H, Ar=radical 29, wherein Z is >C=0, and the chain is attached to position 2 of the tetralin moiety)(Ex. 91). Analogously, but starting from 4-hydroxyxanthene, N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-xanth-4-yloxypropanamine hydrochloride is obtained ((i): R=H, Ar=radical 29, wherein Z is a methylene group, and the chain is attached to position 2 of the tetralin moiety) (Ex. 92).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[F:29][C:28]([F:30])([F:31])[C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=2)[CH:14]=1)=[O:32]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1ccc(CCl)cc1
Yield: 94 %

Procedure:
Using an analogous procedure to that described in Example 37, 4-chloromethylbenzoyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-trifluoromethylbenzamide to give the title compound in 94% yield; NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 4.84 (s, 2H), 7.25 (d, 1H), 7.57 (m, 3H), 7.76 (t, 1H), 7.83 (d, 1H), 7.96 (m, 3H), 8.26 (m, 2H), 9.92 (s, 1H), 10.44 (s, 1H); Mass Spectrum: M−H− 445.
Reaction SMILES: CCOCC.[CH3:6][N:7]([CH2:9][CH2:10][CH2:11]Cl)[CH3:8].[CH3:13][C:14]1([C:19]2[C:29]3[CH2:28][CH2:27][C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[C:24](=[O:34])[C:23]=3[CH:22]=[CH:21][CH:20]=2)[O:18][CH2:17][CH2:16][O:15]1>O1CCCC1>[CH3:13][C:14]1([C:19]2[C:29]3[CH2:28][CH2:27][C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[C:24]([CH2:11][CH2:10][CH2:9][N:7]([CH3:8])[CH3:6])([OH:34])[C:23]=3[CH:22]=[CH:21][CH:20]=2)[O:15][CH2:16][CH2:17][O:18]1
Reactant: CN(C)CCCCl
Reactant: CC1(c2cccc3c2CCc2ccccc2C3=O)OCCO1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CCCC1(O)c2ccccc2CCc2c(C3(C)OCCO3)cccc21
Temperature: 0 °C

Procedure:
Utilizing 1.13 g. of Gilman alloy, 5 ml. of absolute ether, 5.2 g. of dimethylaminoproyl chloride and 5 ml. of absolute tetrahydrofuran, in a similar manner, is obtained the corresponding Grignard compound. After cooling to 0°C., there is added dropwise a solution containing 7.2 g. of 1-(2-methyl-1,3-dioxolan-2-yl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one in 40 ml. of absolute tetrahydrofuran. Subsequently, the mixture is heated for 3 hours at reflux, cooled to about 0°C., hydrolyzed with 4 ml. of water, filtered, and then washed with ether. The ethereal solution is dried over sodium sulfate, filtered and concentrated under reduced pressure, whereby 1-(2-methyl-1,3-dioxolan-2-yl)-10,11-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene is obtained as a yellow oil which is crystallized from 50 ml. of high-boiling petroleum ether and has a melting point of 122°-124°C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH:10]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(Cl)(Cl)Cl>[CH3:7][C:6]([O:5][C:3](=[O:4])[CH2:2][N:10]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C1CNCCNCCNCCN1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CN1CCNCCNCCNCC1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A solution of t-butyl bromoacetate (25.3 g; 130 mmol) in CHCl3 (500 mL) (commercial product) was added dropwise in 7 h to a solution of 1,4,7,10-tetraazacyclododecane (112.3 g; 650 mmol) (commercial product) in CHCl3 (2 L) maintained under nitrogen at room temperature. After 14 h the solution was concentrated to 800 mL, washed with H2O, dried and evaporated to give the desired compound (39 g; 129 mmol). Yield 99%. GC: 92% (area %). K.F.: 0.42%. The 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=3[C:13](=[O:21])[N:12]([CH3:22])[CH2:11][C:10]=12)=[O:5])[CH3:2].[CH:23]1(O)[CH2:28]CC[CH2:25][CH2:24]1>CCO.CCO.CCO.CCO.[Ti]>[Cl:20][C:19]1[C:14]2[C:13](=[O:21])[N:12]([CH3:22])[CH2:11][C:10]3[N:9]([CH:8]=[N:7][C:6]=3[C:4]([O:3][CH:1]3[CH2:25][CH2:24][CH2:23][CH2:28][CH2:2]3)=[O:5])[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: OC1CCCCC1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: [Ti]
Solvent: CCO
Product: CN1Cc2c(C(=O)OC3CCCCC3)ncn2-c2cccc(Cl)c2C1=O
Reaction time: 8 h

Procedure:
A mixture of 8.72 g (27 mmol) of ethyl-7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 2 g (9 mmol) of tetraethyl orthotitanate and 27 g (270 mmol) of cyclohexanol is stirred at 125° overnight, evaporated to dryness, the residue is taken up in chloroform, the chloroform solution is washed successively with 40 ml of 5N hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. By recrystallization from ethanol and ether there is obtained cyclohexyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 208°-209°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[C:10]([OH:15])=[N:11][CH:12]=[CH:13][N:14]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:23]([O:30][C:31](ON1C(=O)CCC1=O)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:30][C:31]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[C:10]([OH:15])=[N:11][CH:12]=[CH:13][N:14]=2)[CH2:3][CH2:2]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: Oc1nccnc1NCC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(CNc2nccnc2O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-[(piperidin-4-ylmethyl)-amino]-pyrazin-2-ol from Step 1 above (0.287 g, 1.021 mmol) in DMF (5 mL) was added triethylamine (0.356 mL, 2.55 mmol), followed by N-(benzyloxycarbonyloxy)succinimide (0.305 g, 1.23 mmol). The resulting reaction mixture was stirred at rt for 15 min, then partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the crude product purified by flash column chromatography (50% EtOAc hexane to 5% MeOH EtOAc) to give an oil which solidified on standing. M.S (M+1): 343.24.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:17]=[CH:16][C:8](/[CH:9]=[N:10]/[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1>CO.C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)C/N=C/c1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CNCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (438 mg, 1.2 mmol) was added to a solution of (E)-methyl 2-(4-methoxybenzylideneamino)acetate (2.0 g, 9.6 mmol) in a mixture of methanol (22 mL) and THF (11 mL) at 0° C. The reaction mixture was stirred 1 hour at room temperature then partitioned between a solution of saturated ammonium chloride (20 mL) and ethyl acetate (30 mL). The aqueous phase was separated and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness. The title compound was obtained as a white oil (1.7 g, 85%).
Reaction SMILES: [Na].Cl[C:3]1[N:8]2[N:9]=[CH:10][CH:11]=[C:7]2[N:6]=[C:5]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:4]=1.[O-:25][CH2:26][CH2:27][CH2:28][CH3:29].[Na+]>C(O)CCC>[CH2:26]([O:25][C:3]1[N:8]2[N:9]=[CH:10][CH:11]=[C:7]2[N:6]=[C:5]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:4]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCC[O-]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Agent: [Na+]
Agent: [Na]
Solvent: CCCCO
Product: CCCCOc1cc(NC(=O)c2ccc(C(C)(C)O)cc2)nc2ccnn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium metal was added to dry butanol (5 mL, 54.6 mmol) at 0° C. then the reaction was raised to room temperature. Then, the next day, a solid precipitated. Stir N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (100 mg, 0.302 mmol) in dry butanol (5 mL). Add the previously made sodium butoxide (58 mg, 0.605 mmol) at 0° C. then raise to room temperature. After stirring overnight, the majority of the reaction was converted to product. Deamination was observed where the amide bond of the compound was cleaved. The compound was filtered and purified by preparatory HPLC 40-50% (MeCN/H2O gradient+0.01% TFA). Received 29.1 mg of a white solid (26%). 1H NMR (DMSO-d6) δ: 11.08 (s, 2H), 8.09 (d, J=2.3 Hz, 2H), 8.01 (d, J=8.6 Hz, 4H), 7.61 (d, J=8.6 Hz, 4H), 7.54 (s, 2H), 6.40 (d, J=2.0 Hz, 2H), 5.19 (s, 2H), 4.46 (t, J=6.4 Hz, 4H), 1.79-1.98 (m, 4H), 1.49-1.62 (m, 4H), 1.46 (s, 12H), 0.99 (t, J=7.5 Hz, 3H). ESI-MS: m/z 369.4 (M+H)+.
Reaction SMILES: [CH:1]12[CH:8]([N:9]([CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:10][C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C1([O:32][C:33]([NH:35][OH:36])=O)C=CC=CC=1.O>C1COCC1>[OH:36][NH:35][C:33]([N:3]1[CH2:4][CH:5]2[CH:8]([N:9]([CH2:10][C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:1]([CH2:7][CH2:6]2)[CH2:2]1)=[O:32]
Reactant: O=C(NO)Oc1ccccc1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1C2CCC1CNC2
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccnc1CN(Cc1ncccc1C)C1C2CCC1CN(C(=O)NO)C2
Yield: 74.5 %

Procedure:
A mixture of (3-aza-bicyclo[3.2.1]oct-8-yl)-bis-(3-methyl-pyridin-2-ylmethyl)-amine (0.064 g, 0.19 mmol) and hydroxylaminecarboxylic acid phenyl ester (PhOCONHOH) (0.058 g, 0.38 mmol) in dry THF (4 mL) was heated at reflux overnight. Water (10 mL) was then added, and the mixture was extracted with EtOAc (20 mL) and CH2Cl2 (2×20 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (100:5:4 CH2Cl2/MeOH/NH4OH), affording the product as a white solid (0.056 g, 75%). 1H NMR (CDCl3) δ 1.51-1.58 (m, 2H), 1.74-1.77 (m, 2H), 2.14 (s, 6H), 2.25 (s, br. 2H), 3.15 (t, 1H, J=4.2 Hz), 3.24-3.29 (m, 2H), 3.37-3.42 (m, 2H), 3.96 (s, 4H), 6.93 (s, br. 1H), 6.98 (dd, 2H, J=4.8, 7.5 Hz), 7.25 (d, 2H, J=7.5 Hz), 8.33 (d, 2H, J=4.8 Hz); 13C NMR (CDCl3) δ 18.93, 26.08, 35.82, 44.58, 57.64, 67.11, 122.19, 132.69, 137.86, 146.39, 157.51, 163.07. ES-MS m/z 396 (M+H). Anal. Calcd. for C22H29N5O2.0.4CH2Cl2: C, 62.65; H, 6.99; N, 16.31. Found: C, 62.50; H, 7.35; N, 16.10.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2(O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH2:11][CH2:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: OC1(c2ccc(Cl)nc2)CCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Clc1ccc(C2=CCCC2)cn1
Temperature: 25 °C
Yield: 88 %

Procedure:
1-(6-Chloropyridin-3-yl)cyclopentanol (2.1 g, 10.5 mmol) was treated with acetic acid (12 mL) and sulfuric acid (4 mL) and the mixture heated to reflux for 30 min. After cooling to room temperature, ice and 2 N NaOH (180 mL) was add and the resulting tan precipitate collected by filtration, washed with H2O and dried giving 2-chloro-5-(cyclopent-1-enyl)pyridine (1.66 g, 88%) as a tan solid: mp 59-60° C., LC/MS (ESI) m/z 179, 1H NMR (300 MHz, CDCl3) δ 8.41 (d, 1H, J=2.4 Hz), 7.66 (dd, 1H, J=8.4, 2.4 Hz), 7.25 (d, 1H, J=8.4 Hz), 6.27 (t, 1H, J=2.1 Hz), 2.69 (bm, 2H), 2.55 (bm, 2H), 2.05 (m, 2H).
Reaction SMILES: S(=O)(=O)(O)O.[BrH:6].[CH:7]1([CH2:13][CH2:14]O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[Br:6][CH2:14][CH2:13][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Br
Reactant: OCCC1CCCCC1
Agent: O=S(=O)(O)O
Product: BrCCC1CCCCC1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
In a 1 l-roundbottom flask equipped with a reflux condenser 164 g concentrated sulphuric acid and 200 g hydrobromic acid (48% in water) were added subsequently under cooling with an ice bath to 88.7 g (0.693 mole) 2-cyclohexyl-ethanol. The mixture was refluxed for 6 h and after cooling to room temperature given to 400 g of ice. The aqueous phase was extracted with 400 ml pentane. The organic layer was washed with a 2 M NaOH-solution and with water, dried over magnesium sulphate, and the solvent was removed in vacuo. The product was distilled in vacuo to yield 112.7 g (85%) of (2-bromo-ethyl)-cyclohexane as a colourless oil. 1H-NMR (400 MHz, CDCl3): δ=3.40 (2H, t, CH2Br), 1.73-1.61 (m, 7H), 1.44 (m, 1H), 1.26-1.11 (m, 3H), 0.92-0.84 (m, 2H) ppm.
Reaction SMILES: P(O[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(OCC)(OCC)=O.[CH:17]([C:19]1[C:20](B(O)O)=[CH:21][S:22][CH:23]=1)=[O:18].ClC1C=CC(CC2SC(C=O)=CC=2)=CC=1>>[CH2:10]([C:20]1[C:19]([CH:17]=[O:18])=[CH:23][S:22][CH:21]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOP(=O)(OCC)OCc1ccccc1
Reactant: O=Cc1cscc1B(O)O
Agent: O=Cc1ccc(Cc2ccc(Cl)cc2)s1
Product: O=Cc1cscc1Cc1ccccc1
Yield: 46 %

Procedure:
The title compound was synthesized from diethyl benzyl phosphate (Org. Lett. 2005, 7, 4875-4878) and 4-formylthiophen-3-ylboronic acid using the conditions to synthesize 5-(4-chlorobenzyl)thiophene-2-carbaldehyde (Example 1.1.a). Purification by prep-TLC (10% heptane/DCM, eluting 3×) yielded 4-benzylthiophene-3-carbaldehyde (204 mg, 46%). 1H NMR (400 MHz, CDCl3) δ ppm 4.29 (s, 2H), 6.83-6.86 (m, 1H), 7.20-7.26 (m, 3H), 7.29-7.34 (m, 2H), 8.12 (d, J=3.22 Hz, 1H), 9.98 (d, J=0.73 Hz, 1H).
Reaction SMILES: [K].C([O:9][C:10]1[CH:15]=[C:14]([CH2:16][CH:17]([CH3:22])[C:18](=[O:21])[CH2:19][CH3:20])[CH:13]=[CH:12][C:11]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1)C1C=CC=CC=1>CCO.O.[Pd]>[OH:9][C:10]1[CH:15]=[C:14]([CH2:16][CH:17]([CH3:22])[C:18](=[O:21])[CH2:19][CH3:20])[CH:13]=[CH:12][C:11]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1
Reactant: CCC(=O)C(C)Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: [K]
Solvent: O
Solvent: CCO
Product: CCC(=O)C(C)Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Reaction time: 0.5 h

Procedure:
To a solution of 5-[2-benzyloxy-4-(2-methyl-3-oxo-pentyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt in 5 mL of EtOH/water (1:1)) is added 20 mg of Degussa Pd/C and the resulting mixture is hydrogenated at 1 atm for 30 min. The catalyst is filtered through Celite and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC to give the title compound: 1H NMR (Acetonitrile-d3) δ 7.30 (d, J=8.0 Hz, 1H), 6.79 (m, 1H), 6.75 (dd, J=8.0, 2.0 Hz, 1H), 4.38 (s, 2H), 2.83 (m, 2H), 2.46 (m, 2H), 2.29 (m, 1H), 1.01 (m, 3H), 0.9 (t, J=7.33 Hz, 3H). (M−1)−=325. HPLC retention time=0.92 min (Method A).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]([C:10]#[N:11])=[CH:8][CH:9]=1)=[O:20]
Reactant: COC(=O)c1ccc(C#N)c(OS(=O)(=O)C(F)(F)F)c1
Reactant: OB(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#N)c(-c2ccccc2)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
4-Cyano-3-(trifluoromethanesulfonyloxy)-benzoic acid methyl ester from step 1 (2.5 g, 8.1 mmol) and phenylboronic acid (2 g, 16.2 mmol) were dissolved in DMF (33 ml) and treated with Et3N (3.1 ml, 17.8 mmol). Argon was bubbled into the solution for 20 min. and then a catalytic amount of PdCl2 (PPh3)2 (285 mg, 0.405 mmol) was added. The reaction mixture was warmed to 90° C. and stirred for 3 hours under argon atmosphere. The reaction was quenched with satd. NaHCO3 (20 mL) and extracted with EtOAc (2×20 mL). The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (10% EtOAc/Hexane) to yield the desired product. FAB MS: 238 m/z (M+ +H)
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[OH:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([C:17]([CH3:20])([CH3:19])[OH:18])([CH2:10]3)[CH2:8]1)[CH2:14]2.C(N(CC)CC)C.O1CCCC1>O>[C:1]([O:18][C:17]([C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][C:7]([OH:6])([CH2:14]3)[CH2:8]1)[CH2:10]2)([CH3:20])[CH3:19])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(O)C12CC3CC(CC(O)(C3)C1)C2
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OC(C)(C)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 23 %

Procedure:
A total of 10 mmole of acrylic chloride was added dropwise to a mixture of 10 mmole of the above-prepared 3-hydroxy-α,α-dimethyl-1-adamantanemethanol, 10 mmole of triethylamine, and 40 ml of tetrahydrofuran ,over about 30 minutes. After the completion of addition, the resulting mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture and the mixture was concentrated, and the concentrate was subjected to column chromatography on a silica gel to yield the title compound in a yield of 23%.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([O:10]CC)[C:7]=1[C:8]#[N:9].CO>O>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([OH:10])[C:7]=1[C:8]#[N:9]
Reactant: CCOc1csc(N)c1C#N
Agent: Cl
Solvent: O
Solvent: CO
Product: N#Cc1c(O)csc1N

Procedure:
A solution of 20 parts by volume of concentrated hydrochloric acid in 100 parts by volume of water is added dropwise to a boiling mixture of 168 parts of 2-amino-3-cyano-4-ethoxythiophene and 500 parts by volume of methanol. The mixture is refluxed for a further 2 hours and diluted with 400 parts by volume of water, and the product is filtered off under suction, washed with water and dried to give 136 parts of 2-amino-3-cyano-4-hydroxythiophene. The sample recrystallized from acetic acid does not melt below 300° C. and has the following analytical values:
Reaction SMILES: [CH2:1]([O:4][C:5](Cl)=[O:6])[CH2:2]Cl.Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[C:12]([F:18])[CH:11]=1.C(N(CC)CC)C.CC(C)([O-])C.[K+]>C1COCC1.C(Cl)Cl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:2][CH2:1][O:4][C:5]2=[O:6])=[C:12]([F:18])[CH:11]=1
Reactant: O=C(Cl)OCCCl
Reactant: NCc1ccc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCCN1Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-chloroethyl chloridocarbonate (114 μL, 1.1 mmol) was added to a mixture of 1-(4-bromo-2-fluorophenyl)methanamine hydrochloride (0.240 g, 1.0 mmol) and triethylamine (293 μL, 2.1 mmol). The mixture was stirred at RT for 3 h, and then 1M of potassium tert-butoxide in THF (1.2 mL) was added. The mixture was stirred overnight at RT, diluted with methylene chloride, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product which was directly used in next step without further purification. LCMS: (M+H)=275.9/273.9.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:23]=[CH:22][C:13]([CH2:14][C:15]2[C:20](O)=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:12]([F:24])[CH:11]=1.C(OCC)(=O)C>CN(C)C=O>[Br:9][C:10]1[CH:23]=[CH:22][C:13]([CH2:14][C:15]2[C:20]([O:4][CH3:1])=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:12]([F:24])[CH:11]=1
Reactant: Oc1cccnc1Cc1ccc(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccnc1Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
Potassium carbonate (38.7 mg, 0.280 mmol) and methyl iodide (10.5 μl, 0.168 mmol) were added to a solution of the compound of Example B245 (15.8 mg, 0.0560 mmol) in dimethylformamide (1 ml), and this reaction mixture was stirred at room temperature for 2 hours. After ethyl acetate was added, the reaction mixture was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (14.0 mg).