Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[S:18]([C:21]2[CH:29]=[CH:28][C:27]3[N:26]4[CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][N:33]=[C:25]4[C:24]4([O:40]CCCO4)[C:23]=3[CH:22]=2)(=[O:20])=[O:19])(=O)=O)=CC=1.[CH:41]1([NH2:47])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>C1COCC1>[CH:41]1([NH:47][CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[S:18]([C:21]2[CH:29]=[CH:28][C:27]3[N:26]4[CH2:30][C:31]([CH3:34])([CH3:35])[CH2:32][N:33]=[C:25]4[C:24](=[O:40])[C:23]=3[CH:22]=2)(=[O:19])=[O:20])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: NC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C2(OCCCO2)C2=NCC(C)(C)CN23)cc1
Solvent: C1CCOC1
Product: CC1(C)CN=C2C(=O)c3cc(S(=O)(=O)N4CCC[C@H]4CNC4CCCCC4)ccc3N2C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
To a solution of {(2S)-1-[(3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-yl)sulfonyl]pyrrolidin-2-yl}methyl 4-methylbenzenesulfonate (0.100 g, 0.170 mmol) in THF (2 mL) was added cyclohexylamine (0.034 g, 0.340 mmol) and the reaction was stirred at 70° C. overnight. Additional cyclohexylamine (0.088 g, 0.850 mmol) was added to the reaction and stirred at 100° C. for 2 days. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated and purified on Biotage Si 12+M cartridge silica gel eluting with acetone/hexane (35/65). The resulting product was dissolved in CH2Cl2 (2 mL) and methanesulfonic acid (2 mL) was added and the solution was stirred at rt overnight. The reaction mixture was poured onto ice, basified to pH 11 with ammonium hydroxide and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated and purified on Biotage Si 12+M cartridge silica gel eluting with acetone/hexane (35/65) to give the title compound as a yellow foam (0.036 g, 46%). NMR (400 Mz, DMSO-d6): consistent. MS: (ESI+) m/z 459.3 [M+H].
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([OH:11])[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]([I:22])=[CH:20][N:19]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17]=2[N:18]=1>C1COCC1>[Cl:12][C:13]1[N:14]=[C:15]([O:10][CH:7]2[CH2:8][CH2:9][C:4]([CH3:3])([OH:11])[CH2:5][CH2:6]2)[C:16]2[C:21]([I:22])=[CH:20][N:19]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17]=2[N:18]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Reactant: CC1(O)CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(O)CCC(Oc2nc(Cl)nc3c2c(I)cn3COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 1.36 equiv) in dry THF (0.68 M) under nitrogen atmosphere was added 1-methylcyclohexane-1,4-diol (1 equiv). The reaction mixture was stirred at room temperature for 30 min before a solution of 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (0.9 equiv,) in dry THF (0.45 M) was added. The mixture was stirred at room temperature for 2 h. The reaction was monitored by thin layer chromatography. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography (0-30% ethyl acetate in petroleum ether) to afford the title compound as a white solid (78% yield). MS (ESI) m/z 538.4 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:7][C@@H:6]2[C@@H:8]([OH:11])[CH2:9][O:10][C@@H:5]2[C@@H:4]1[OH:12].[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1>CN(C=O)C>[CH2:19]([O:12][CH:4]1[CH:5]2[O:10][CH2:9][CH:8]([OH:11])[CH:6]2[O:7][CH2:3]1)[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC1COC2C(OCc3ccccc3)COC12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a suspension of NaH (60% mineral oil suspension, 3.28 g, 82.1 mmol) in DMF (135 mL) at 0° C. was added a solution of isobide (10.00 g, 68.4 mmol) in DMF (10 mL) dropwise. After addition, the reaction mixture was stirred at 0° C. for 30 min, then BnBr (14.04 g, 82.1 mmol) was added too. The resulting mixture was allowed to stir at rt overnight and concentrated in vacuo. The residue was dissolved in water (100 mL), and extracted with EtOAc (200 mL×3). The combined organic phases were washed with brine (200 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10) to give the title compound as yellow oil (10.36 g, 64.1%).
Reaction SMILES: BrCCCC[N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].C1(C2C=CC(O)=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:10]1(=[O:11])[NH:6][C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: Oc1ccc(-c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 85 °C
Reaction time: 16 h
Yield: 162.3 %

Procedure:
A mixture of N-(4-bromobutyl)phthalimide (14.1 g, 50 mmol), 4-phenylphenol (8.5 g, 50 mmol), and potassium carbonate (15.0 g, 108 mmol) in DMF (75 ml) was stirred under nitrogen for 16 hours at 85° C., then water (200 ml) was added dropwise to the cooled solution. The precipitate was collected by filtration, and recrystallized from methanol-water to provide N-[4-(1,1'-bi-phenyl]-4-yloxy)butyl]phthalimide as an off-white solid (11.94 g, 64% yield), mp 114°-115° C.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([O:8][C:9]([C:11]1[CH:12]([CH3:25])[CH2:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH+:17]([CH3:24])[C:16]=12)=[O:10])[CH3:7]>CC(N(C)C)=O.[Pd]>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([O:8][C:9]([C:11]1[C:12]([CH3:25])=[CH:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH+:17]([CH3:24])[C:16]=12)=[O:10])[CH3:7]
Reactant: CCOC(=O)C1=C2N(CCC1C)c1ccccc1[NH+]2C
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C1=C2N(CC=C1C)c1ccccc1[NH+]2C

Procedure:
4-Ethoxycarbonyl-1,2-dihydro-3,5-dimethyl-5H-pyrido[1,2-a]benzimidazolium perchlorate (2.22g; 0.006 mole) is refluxed for an hour with stirring in (DMA) dimethylacetamide (40ml) containing (Pd/C) palladium on carbon (10%) (about .4g). The mixture is cooled, filtered, and poured into stirred ether. After an hour the solid is filtered, washed with ether, and dried to give 1.58g (71.5%). Recrystallized from ethanol to give 1.18g (53.5%); m.p. 242°-245° d.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[I:23])[O:9][C:8]1=[O:24].[N+:34]([O-])([OH:36])=[O:35].O>CCOC(C)=O>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([N+:34]([O-:36])=[O:35])[C:14]=2[I:23])[O:9][C:8]1=[O:24]
Reactant: O=[N+]([O-])O
Reactant: C[C@@H]1[C@@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1[C@@H](c2cc(C(F)(F)F)cc([N+](=O)[O-])c2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4R,5R)-3-[3,5-Bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one was added in portions to 2 mL of fuming nitric acid at 0° C. The reaction mixture was stirred overnight at r.t., and then heated to 75° C. for 4 h. The reaction mixture was cooled and then added dropwise to a rapidly stirred mixture of 10 mL of water and 10 mL of EtOAc. The phases were separated and the organic phase was washed with 10 mL each of saturated NaHCO3 and brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 5% EtOAc in hexanes followed by a linear gradient of 5→100% EtOAc in hexanes over 10 CV, to provide the title compound. Mass spectrum (ESI) 643 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[C:15]1([C:21]2[C:29]3[C:28]([N:30]4[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]4)=[N:27][CH:26]=[N:25][C:24]=3[S:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:7])[CH2:8][NH:36][CH:33]1[CH2:34][CH2:35][N:30]([C:28]2[C:29]3[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:22][S:23][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:31][CH2:32]1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Reactant: COc1ccc(OCC2CO2)c(F)c1
Product: COc1ccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)c(F)c1
Yield: 40 %

Procedure:
Synthesis followed SP6 (3 h), using 300 μmol 2-((2-fluoro-4-methoxyphenoxy)methyl)oxirane and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-methylated intermediate 1-(2-fluoro-4-methoxyphenoxy)-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol upon purification by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) with 40% yield. Product was obtained by O-demethylation according to SP12 (1 h) with 37% yield (LCMS: detected [M+1]=495.2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH2:13]O)=[CH:11][N:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>C1COCC1>[Br:35][CH2:13][C:10]1[O:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:12][CH:11]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cnc(-c2ccccc2Cl)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccccc1-c1ncc(CBr)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
181 mg (0.77 mmol) of the compound from Example 50A and 242 mg (0.92 mmol) of triphenyl-phosphine were dissolved in 4 ml of THF, and 306 mg (0.92 mmol) of carbon tetrabromide were added at RT. The mixture was then stirred at RT for 16 h. For work-up, the mixture was filtered through 20 g of kieselguhr, the filter residue was rinsed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [Method 19]. This gave 112 mg (42% of theory) of the target compound in a purity of 80% which were immediately reacted further.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]2[C:15]([CH3:27])([CH3:26])[C:16](=[O:25])[N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:18]=2)[CH:4]=1.[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:45])=[C:40]([CH:44]=1)[C:41](O)=[O:42])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:45])=[C:40]([C:41]([N:22]2[CH2:23][CH2:24][CH:19]([N:17]3[C:16](=[O:25])[C:15]([CH3:27])([CH3:26])[C:14]([C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:11]5[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=5[CH:6]=4)=[N:18]3)[CH2:20][CH2:21]2)=[O:42])[CH:44]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: COc1cc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc2c1OC(C)(C)C2
Product: COc1cc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C2(C)C)cc2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B12) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([NH2:21])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.[C:22]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+]>O1CCCC1.C(O)(=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([NH:21][CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: N#Cc1cc(N)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cc(NC2CCCC2)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Temperature: 60 °C
Yield: 39 %

Procedure:
A mixture of 3-(5-fluoropyrid-2-yl)-5-(3-amino-5-cyanophenyl) -1,2,4-oxadiazole (30 mg, 0.11 mmol), cyclopentanone (24 μL, 0.26 mmol), sodium cyanoborohydride, 1.0 M solution in tetrahydrofuran, (128 AL, 0.12 mmol) in acetic acid (4 mL) was heated at 60° C. for 1 hour. After cooling, the reaction mixture was diluted with ethyl acetate and then washed with water (2X) and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography using 20% ethyl acetate/hexanes afforded 15 mg (39%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-cyclopentylaminophenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.69 (d, 1H), 8.25 (m, 1H), 7.79 (s, 1H), 7.61 (m, 2H), 6.99 (s, 1H), 4.17 (d, 1H), 3.88 (m, 1H), 2.10 (m, 1H), 1.74 (s, 2H), 1.50 (m, 1H), 1.27 (m, 2H), 0.87 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5]([N:8]=CN(C)C)=[N:6][CH:7]=1.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][C:44]([NH:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])=[CH:7][N:6]=1
Reactant: COc1cc(-c2csc3c(N)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: O=C=Nc1ccccc1
Product: COc1cc(-c2csc3c(NC(=O)Nc4ccccc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(7-amino-4-{[(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide and phenyl isocyanate using General Procedure N followed by General Procedure M. 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 9.07 (s, 1H), 8.58 (s, 1H), 8.09 (s, 1H), 8.06 (d, 1H), 7.73 (m, 2H), 7.60 (d, 1H), 7.49 (d, 2H), 7.36 (s, 1H), 7.30 (m, 4H), 7.14 (m, 2H), 7.00 (t, 1H), 6.10 (br, 2H), 4.04 (s, 3H), 3.93 (s, 3H); MS: (MH)+ 563.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:22]([NH2:24])[CH3:23]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][NH:24][CH2:22][CH3:23])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCN
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CCNCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Ethylamine were converted to yield {3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-ethyl-amine as white solid, MS: 391 (MH+, 1Br).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][C:9]=2[CH:13]=O)=[CH:4][CH:3]=1.Cl.[NH2:16]O.C([O-])(=O)C.[Na+]>C(O)C.C(OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][C:9]=2[C:13]#[N:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccoc2C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(-c2ccoc2C#N)cc1
Temperature: 65 °C
Yield: 89.8 %

Procedure:
A mixture of 3-(4-methylphenyl)furane-2-carbaldehyde (1.0 g), hydroxylamine hydrochloride (560 mg), and sodium acetate (660 mg) in 60% aqueous ethanol (10 ml) was stirred for one and half hours at 65° C. The mixture was concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried, and concentrated in vacuo to give a yellow solid. A mixture of the solid and sodium acetate (56 mg) in acetic anhydride (10.5 ml) was refluxed for 5 hours and then evaporated in vacuo. The residue was purified by column chromatography on silica gel (elution by n-hexane/ethyl acetate=15/1) to yield 3-(4-methylphenyl)furane-2-carbonitrile (884 mg) as a yellow oil.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([F:17])[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:13][CH:12]=2)=[C:7](O[SiH](C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].[O:61]1CCCC1>>[F:17][C:15]1[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:13][CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([OH:61])=[CH:6][CH:7]=2)[N:16]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(C)(C)C)cc2O[SiH](c2ccccc2)c2ccccc2)nc1F
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Product: CCCCCCCCOc1ccc(-c2ccc(O)cc2)nc1F

Procedure:
4.30 g (8.00 mmol) of 6-(4-tert.-butyldiphenylsilyloxyphenyl)-2-fluoro-3-octyloxypyridine are stirred in 16 ml of a 1-molar tetrabutylammonium fluoride solution in tetrahydrofuran and 50 ml of tetrahydrofuran at room temperature for 2 hours. Sodium chloride solution is then added, the resulting mixture is extracted with ether, the ether phase is washed with sodium chloride solution, dried over sodium sulfate, evaporated to dryness, and the residue is purified by chromatography (silica gel, 8:2 hexane/ethyl acetate), giving 2.16 g of 2-fluoro-6-(4-hydroxyphenyl)-3-octyloxypyridine. ##STR47##
Reaction SMILES: [C:1]([NH:11][CH:12]([C:18](=[O:20])[CH3:19])[CH2:13][C:14]([O:16]C)=[O:15])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:19][C:18]1[O:20][C:1]([CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[N:11][C:12]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)CC(NC(=O)C=Cc1ccccc1)C(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oc(C=Cc2ccccc2)nc1CC(=O)O

Procedure:
A mixture of methyl 3-cinnamoylamino-4-oxovalerate (2.2 g), phosphorus oxychloride (2.2 ml) and toluene (24 ml) was refluxed with stirring for an hour. The solvent was distilled off and the residue was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and ethanol (8 ml) and 2N sodium hydroxide (8 ml) were added to the residue. The mixture was stirred for 30 minutes and adjusted to pH 2 with diluted hydrochloric acid. The resulting crystalline precipitate was collected by filtration to give 5-methyl-2-styryl-4-oxazoleacetic acid; yield 1.50 g (77.3%). Recrystallization from ethanol gave pale brown needles melting at 182°-183° C. The IR and NMR spectra of this product were in good agreement with those of the compound obtained in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][CH2:26][NH:27][C:28](=[O:42])[C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][N:38]=[C:37](Cl)[N:36]=4)=[CH:31][CH:30]=3)[CH:23]=2)[NH:18][CH:17]=1)#[N:15]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:37]2[N:36]=[C:35]([C:32]3[CH:33]=[CH:34][C:29]([C:28](=[O:42])[NH:27][CH2:26][CH2:25][C:22]4[CH:23]=[C:24]5[C:19](=[CH:20][CH:21]=4)[NH:18][CH:17]=[C:16]5[C:14]#[N:15])=[CH:30][CH:31]=3)[CH:40]=[CH:39][N:38]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3ccc(C(=O)NCCc4ccc5[nH]cc(C#N)c5c4)cc3)n2)CC1

Procedure:
Using piperazine-1-carboxylic acid tert-butyl ester and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 1.44 (s, 9H); 2.98 (t, 2H, J=7 Hz); 3.45 (bs, 4H); 3.56 (m, 2H); 3.83 (bs, 4H); 7.18 (d, 1H, J=8 Hz); 7.31 (d, 1H, J=5 Hz); 7.48 (d, 1H, J=8 Hz); 7.51 (s, 1H); 7.94 (d, 2H, J=8 Hz); 8.22 (m, 3H); 8.49 (d, 1H, J=5 Hz); 8.70 (bt, 1H); 12.12 (bs, 1H). MS (ion spray) m/z 552 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]2([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])OCC[O:43]2)[C@:22]([CH2:31][CH2:32][F:33])([OH:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].O.S(=O)(=O)(O)O.C(OCC)(=O)C>C(#N)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:43])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C@:22]([CH2:31][CH2:32][F:33])([OH:30])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCF)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCF)C(=O)O)C(=O)OC)cc1
Reaction time: 26 h
Yield: 12.6 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-(2-fluoro-ethyl)-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-undec-4-enoate (21.0 mg, 0.0282 mmol) was dissolved in acetonitrile (1.0 mL), and water (0.01 mL, 0.556 mmol) and sulfuric acid (0.005 mL, 0.0938 mmol) were then added at room temperature. After stirring for 26 hours, ethyl acetate (10 mL) and water (10 mL) were added and the mixture was separated. The ethyl acetate layer was washed with a saturated aqueous solution (10 mL) of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (diol, n-hexane/acetone=4/1) to obtain 2.3 mg of the title compound (0.00356 mmol, yield 13%) as a minor component.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:22]=[O:23].[OH-].[Na+]>O>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH:12]([CH2:22][OH:23])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: Fc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCC1CN(Cc2ccccc2)CC=C1c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 78.3 %

Procedure:
4.5 g (16.8 mmol) of 1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine were suspended in 55 ml of water, then partially dissolved by the addition of 70 ml of concentrated hydrochloric acid, 1.36 g (45.3 mmol) of paraformaldehyde were added and the mixture was stirred at 100° C. for 5 hours. After cooling to room temperature the mixture was adjusted to pH 5-6 with sodium hydroxide solution and the product was extracted twice with 100 ml of ethyl acetate. The organic phases were washed once with 100 ml of water, dried over magnesium sulphate, filtered and concentrated in a water-jet vacuum. The thus-obtained crude product was chromatographed on silica gel with hexane and ethyl acetate as the eluent (sic). There were obtained 3.91 g (78% of theory) of (RS)-[1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridin-3-yl]-methanol; MS: 297 (M)+.