Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]([CH3:19])[CH2:13]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:22][Mg]Br>O1CCCC1>[OH:3][C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][C@@H:14]([CH3:19])[CH2:15][C@H:16]([CH3:18])[CH2:17]2)=[CH:6][CH:5]=1)([CH3:22])[CH3:2]
Reactant: CC(=O)c1ccc(OCCCN2C[C@@H](C)C[C@H](C)C2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: C[C@H]1C[C@H](C)CN(CCCOc2ccc(C(C)(C)O)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of trans-1-[3-(4-acetylphenoxy)propyl]-3,5-dimethylpiperidine (289 mg) in tetrahydrofuran (1 mL) is stirred at room temperature under anhydrous atmosphere and a 2.61 M solution of methylmagnesium bromide in tetrahydrofuran (400 μL) is added dropwise. The mixture is stirred at room temperature for 3 h and quenched with a saturated aqueous solution of ammonium chloride. The solution is extracted with ethyl acetate and the combined extracts washed with water, dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel with dichloro-methane/methanol 95/5 as eluent. Fractions containing the expected product are pooled and salted with 20 mg of oxalic acid to give 70 mg of trans-1-{3-[4-(1-hydroxy-1-methylethyl)-phenoxy]propyl}-3,5-dimethylpiperidine, oxalate as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2O[C:10]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]#[N:24])=[CH:18][C:17]=3[CH3:25])=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.CC1(C)OO1.O.[NH2:32][NH2:33]>CC(C)=O.CO>[CH3:1][C:2]1([C:7]2[N:33]=[N:32][C:10]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]#[N:24])=[CH:18][C:17]=3[CH3:25])=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1
Reactant: NN
Reactant: Cc1cc(C#N)cc(C)c1OCCCc1ccc(C2(C)OCCO2)o1
Agent: CC1(C)OO1
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: Cc1cc(C#N)cc(C)c1OCCCc1ccc(C2(C)OCCO2)nn1
Yield: 47 %

Procedure:
Following a procedure similar to that described in Example 3c, 5-(2-methyl-1,3-dioxolan-2-yl)-2-[3-(2,6-dimethyl-4-cyanophenoxy)-propyl]furan; (1.05 g; 3.08 mmol), 48 mL (0.06M) of dimethyldioxirane in acetone, and 10 mL of acetone were reacted. The resulting product was disolved in methanol and reacted with 85% hydrazine hydrate (0.15 mL; 4.49 mmol) then purified by chromatography on silica gel with 65% ethyl acetate/hexane to afford 0.511 g (47%) of 6-(2-methyl-1,3-dioxolan-2-yl)-3-[3-(2,6-dimethyl-4-cyanophenoxy)propyl]-pyridazine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]1[O:21][CH:6]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Pd].O1CCOCC1>[OH:21][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: CCOC(=O)C1OC1c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Yield: 80 %

Procedure:
A mixture of ethyl-2,3-epoxy-3-(4-benzyloxyphenyl)propionate of the formula (9) (125 g) obtained according to the procedure described in step (ii) above, 5% Pd/C (12.5 g) and 1,4-dioxane (750 ml) was hydrogenated at room temperature at 5–10 psi of hydrogen pressure for a period of 10–15 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered and the solvent was removed under reduced pressure to afford the title compound of the formula (10) (100–105 g, 80–83%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:32].[Na+].OP([O-])(O)=O.[Na+]>C(#N)C.O.C(O)(C)(C)C>[C:21]([NH:20][CH2:19][CH2:18][O:17][C:16]1[CH:24]=[CH:25][C:13]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[Cl:1])[NH:8][CH:7]=[C:6]3[C:11]([OH:32])=[O:12])=[CH:14][CH:15]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)NCCOc1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC#N
Product: CC(=O)NCCOc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 0 °C
Reaction time: 40 h
Yield: 25.7 %

Procedure:
To a solution of N-{2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]ethyl}acetamide (80 mg, 0.23 mmol) in acetonitrile (3 mL) was added tert-butanol (3 mL) and 2-methyl-2-butene (1.89 mL). The reaction mixture was cooled to 0° C., and treated with a solution of sodium chlorite (452 mg, 6.74 mmol) and sodium phosphate monobasic (930 g, 6.74 mmol) in water (3 mL) dropwise. The reaction mixture was stirred at room temperature for 40 h. The reaction mixture was quenched with sodium sulfite and concentrated in vacuo to give a solid. The crude product was washed with DMF and the filtrate was concentrated in vacuo to give a brown residue, which was purified by prep-HPLC to give 5-{4-[2-(acetylamino)ethoxy]phenyl}-6-chloro-1H-indole-3-carboxylic acid (22 mg, 26%) as an off-white solid. MS (ES+) 373.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1 H), 8.14 (br. s., 1 H), 8.06 (s, 1 H), 7.93 (s, 1 H), 7.62 (s, 1 H), 7.34 (d, 2 H), 7.02 (d, 2 H), 4.03 (t, 2 H), 3.45-3.43 (m, 2 H), 1.84 (s, 3 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=[C:9]2[C:17]([OH:19])=[O:18])([O-:3])=[O:2].[CH2:20](O)[CH3:21]>[H][H].ClCl>[CH2:20]([O:18][C:17]([C:9]1[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)=[O:19])[CH3:21]
Reactant: CCO
Reactant: [H][H]
Reactant: O=C(O)c1ccc(C(=O)O)c2c([N+](=O)[O-])cccc12
Agent: ClCl
Product: CCOC(=O)c1ccc(C(=O)O)c2c([N+](=O)[O-])cccc12

Procedure:
52 parts of 8-nitro-naphthalene-1,4-dicarboxylic acid are dissolved in 700 parts of absolute ethyl alcohol and the solution is boiled under reflux for 12 hours whilst continuously passing in hydrogen chlorine gas. The resulting solution is evaporated in vacuo. The 4-ethoxycarbonyl-8-nitro-naphthalene-1-carboxylic acid of the formula ##STR14## which is obtained in this way, melts at 178° to 180°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH3:24][Mg]Cl>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])([CH3:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: C[Mg]Cl
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(C)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
6-Methoxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (300 mg, 0.974 mmol) obtained in Example 1 was dissolved in THF and 1.2 equivalents of methylmagnesium chloride were added thereto, followed by stirring for 3 hrs at 0° C. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 126 mg of the titled compound (yield: 38%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=2)[C:9]([CH3:21])([CH3:20])[C:8]1=[O:22].[OH-].[Na+].CO>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=2)[C:9]([CH3:20])([CH3:21])[C:8]1=[O:22]
Reactant: COCCCCN1C(=O)C(C)(C)c2ccc(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCCCN1C(=O)C(C)(C)c2ccc(C(=O)O)cc21
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To methyl 1-(4-methoxybutyl)-3,3-dimethyl-2-oxoindoline-6-carboxylate (480 mg) were added 2N aqueous NaOH solution (5 ml), MeOH (5 ml), and THF (5 ml), and the mixture was stirred at 65° C. for one hour. After the reaction was complete, the solvent was concentrated, and to the resultant was added dropwise 2N aqueous hydrochloric acid solution. The precipitated crystals were extracted with ethyl acetate, and this ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue (400 mg) was used in the subsequent reaction without further treatment.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:60]1([CH2:66][CH2:67][NH2:68])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][CH2:67][CH2:66][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: NCCc1ccccc1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CC[C@H](C(=O)NCCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 2-phenylethanamine (58.0 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to give the yellow title compound (198 mg). LC-MS (ES) m/z=459 [M+H]+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4N(C)N=C(C)C=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:39])=[C:36]([OH:38])[CH:37]=1>C1COCC1>[OH:38][C:36]1[CH:37]=[C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:22])[CH3:23])=[CH:16][CH:15]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])[CH:33]=[CH:34][C:35]=1[CH3:39]
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C)n1
Reactant: Cc1ccc(N)cc1O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(C)c(O)c2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 29, 70 mg, 0.217 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (32 mg, 0.260 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜2 mL of i-prOH affording the title compound in 69% yield (0.064 g, 0.1497 mmol).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.[CH2:34]([O:41][CH2:42][CH2:43]I)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([O:41][CH2:42][CH2:43][O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: ICCOCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 22 (j)] with 2-(benzyloxy)-ethyl iodide [Helv.Chim.Acta Vol.71, (1988), 2039] there was obtained tert-butyl (3RS,4RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless foam; MS: 599 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C.CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[N:10]([CH3:23])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(-c3ccc(F)cc3)c[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(-c3ccc(F)cc3)cn(C)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 119.9 %

Procedure:
To a solution of compound 53d (300 mg, 0.78 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 68.9 mg, 1.72 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, then CH3I (0.053 mL, 0.86 mmol) was added and stirring continued at 0° C. for another 1 h. The resulting mixture was diluted with EtOAc and water. The organic layer was washed with brine and concentrated. The residue was recrystallized from heptane, filtered and dried the solid to give compound 53f (265 mg) as a light yellow solid. MS m/z (M+H+) 284.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][CH:9]([CH3:11])[CH3:10])[C:3]=1[CH2:12][OH:13]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:12][OH:13].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][CH:9]([CH3:11])[CH3:10])[C:3]=1[CH:12]=[O:13]
Reactant: CC(C)Nc1cccc(Cl)c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)Nc1cccc(Cl)c1C=O
Product: Nc1cccc(Cl)c1CO

Procedure:
A mixture of [2-chloro-6-(isopropylamino)phenyl]methanol, 5-chloro-2,2-dimethyl-1,4-dihydro-2H-3,1-benzoxazine (2.7 g, ratio; 1:1, step 2) and manganese dioxide (3.9 g, 33.8 mmol) in toluene (50 mL) was stirred at reflux temperature for 16 h. The mixture was filtrated through a pad of Celite and the filtrate was concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:30) to give 1.2 g (45% from (2-amino-6-chlorophenyl)methanol) of the title compound as a yellow solid.
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:20]1[CH:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH2:2]([N:9]([CH2:21][CH:22]([OH:20])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Fc1ccccc1OCC1CO1
Reactant: Oc1ccc(OCCNCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: Oc1ccc(OCCN(Cc2ccccc2)CC(O)COc2ccccc2F)cc1

Procedure:
A mixture of N-benzyl-2-(p-hydroxyphenoxy)ethylamine hydrochloride (see Example 1) (5.6 g), 1,2-epoxy-3-o-fluorophenoxypropane (3.6 g) and anhydrous potassium carbonate (2.7 g) was heated under reflux in propan-2-ol (100 ml) for 24 hours. The reaction mixture was cooled, the solid removed by filtration and the solvent evaporated from the filtrate. The residual oil was purified by chromatography on silica eluting with 1% v/v methanol in dichloromethane to give N-benzyl-N-(2-p-hydroxyphenoxyethyl)-3-o-fluorophenoxy-2-hydroxypropylamine as a colourless oil; NMR: 2.27-3.15 (m, 4H, CH2NCH2), 3.8 (dd,2H, NCH2Ph), 3.9-4.2 (m,5H, OCH2.CHOH, o-F-Ph.OCH2), 6.7 (s, 4 aromatic H), 6.8-7.1 (m, 4 aromatic H), 7.3 (m,5H, CH2Ph).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[CH:20]1[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27].P(=O)(O)(O)O>C1(C)C(C)=CC=CC=1.O>[CH3:4][C:3]1([CH3:5])[C:23]2[C:22](=[C:21]([CH3:27])[CH:20]=[C:25]([OH:26])[CH:24]=2)[CH2:1][CH2:2]1
Reactant: Cc1cccc(O)c1
Reactant: C=CC(=C)C
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1cc(O)cc2c1CCC2(C)C
Reaction time: 8 h

Procedure:
449 of isoprene, stabilized with 1.35 g of phenothiazine, were added dropwise over the course of 7 hours to a solution of 648 g of m-cresol, 77 g of 85% strength phosphoric acid and 6 ml of water in 1.44 liters of xylene at 110° C. To complete the reaction, stirring was continued overnight at 110° C. After cooling, the acid phase was separated off and extracted by shaking with toluene. The combined organic phases were washed until neutral. Fractional distillation gave 252 g of 3,3,7-trimethyl-5-hydroxy-indane; boiling point 151°-155° C/18 mm Hg; melting point 80° - 81° C. ##STR37##
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24](O)=[O:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([N:12]1[CH2:11][CH2:10][N:9]([C:4]2[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13]1)=[O:25]
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: CC1CCCCC1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1CCCCC1C(=O)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 45 %

Procedure:
Coupling of 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol) with 2-methylcyclohexanecarboxylic acid (100 mg, 0.70 mmol) was carried out according to a similar procedure described for example 19A using N,N-dimethylformamide (1 mL) as solvent and benzotriazole-1 yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent. 1-[(2-methylcyclohexyl)carbonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine was obtained in 45% yield (112 mg) as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=2[CH:17]=1.B([O-])([O-])O[C:20]1[S:21][CH:22]=[C:23]([CH3:25])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[C:34]1(C)C(CCO)=CC=C[CH:39]=1.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][S:21][C:20]1[CH:39]=[CH:34][C:25]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=3[CH:17]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccccc1CCO
Reactant: Cc1csc(OB([O-])[O-])c1
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2OCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C1=Cc2cc(-c3ccc(SC)cc3)ccc2OCC1
Temperature: 25 °C

Procedure:
Under argon atmosphere, a solution of ethyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (1.0 g), 4-methyl-thiophenyl borate (622 mg) and potassium carbonate (0.93 g) in toluene-ethanol-water (30-3-3 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakistriphenyl-phosphinepalladium (117 mg), and the mixture was refluxed for 16 hours. To the reaction mixture was added tetrakistriphenyl-phosphinepalladium (0.13 g), and the mixture was refluxed for 24 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:10) to give ethyl 7-(4-methylthio-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (442 mg) as colorless crystals.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[C:11](#[N:13])[CH3:12]>>[CH:5]1([C:3](=[O:4])[CH2:12][C:11]#[N:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)C1CCCCC1
Reactant: CC#N
Product: N#CCC(=O)C1CCCCC1

Procedure:
The title compound was prepared in analogy to example 105 step A from cyclohexanecarboxylic acid methyl ester and acetonitrile. Yellow liquid. MS (ESI): 150.2 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20]C1C=CC(N)=CC=1.N1C=CC=CC=1C=O>>[CH3:19][O:20][C:7]1[CH:6]=[CH:5][C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)=[CH:3][CH:2]=1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Reactant: COc1ccc(N)cc1
Agent: O=Cc1ccccn1
Product: COc1ccc(-n2nnc(-c3ccccn3)n2)cc1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 4-methoxyaniline (41.8 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(4-methoxyphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.