Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[OH-].[K+].[C:12]1([CH:22]=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.O>CO>[I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC1N(C)C=C[NH+]1C
Reactant: O=Cc1cccc2ccccc12
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1C=C[NH+](C)C1C=Cc1cccc2ccccc12

Procedure:
A mixture of 6.0 g of 1,2,3-trimethyl-1H-imidazolium iodide, 1 g of potassium hydroxide and 6 ml of 1-naphthaldehyde in 25 ml of methanol is refluxed for 15 minutes during which time a precipitate is formed. The reaction mixture is cooled and 5 ml of water is added. The solid is filtered off, dried, and crystallized from absolute ethanol to yield 3.7 g of the title compound, melting point 251°-253° C.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(COS(C)(=O)=O)C(=O)N(CC(C)C)N=1.[Cl:26][C:27]1[CH:54]=[CH:53][C:30]([CH:31]=[CH:32][CH2:33][N:34]2[C:39](=[O:40])[C:38]([C:41]([O:43]C)=[O:42])=[CH:37][C:36]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[C:47]([CH3:52])[CH:46]=3)=[N:35]2)=[CH:29][CH:28]=1>>[C:41]([C:38]1[C:39](=[O:40])[N:34]([CH2:33][CH:32]=[CH:31][C:30]2[CH:53]=[CH:54][C:27]([Cl:26])=[CH:28][CH:29]=2)[N:35]=[C:36]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[C:47]([CH3:52])[CH:46]=2)[CH:37]=1)([OH:43])=[O:42]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)ccc1F
Yield: 86.2 %

Procedure:
Following the procedure of Example 1 (7), 2-(4-chloro-cinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as a yellow crystalline powder (yield: 86.2%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2)(=O)=O.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[Sn](CCCC)(CCCC)CCCC.[Cl-].[Li+].[Cl-].[F-].[NH4+]>CN(C)C=O.[Ag]=O.C(OCC)(=O)C>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cccc1F
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: O=[Ag]
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(-c3c(F)cccc3F)ccc21
Temperature: 120 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
1.00 g (3.40 mmol) of 3,4-dihydro-6-trifluoromethylsulfonyloxy-1(2H)-naphthalenone was dissolved in 10 ml of N,N-dimethylformamide in an argon atmosphere, and 2.05 g (5.10 mmol) of 2,6-difluorophenyltributyltin, 0.43 g (11.0 mmol) of lithium chloride, 0.12 g (0.17 mmol) of bistriphenylphosphinepalladium chloride and 0.04 g (0.17 mmol) of silver oxide were added to the solution. The mixture was stirred at 120° C. for 1 hour. The reaction product was cooled to room temperature. Ethyl acetate and a 2M-ammonium fluoride aqueous solution were added thereto, followed by stirring the mixture at room temperature overnight. The precipitate was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica-gel column chromatography (eluent: a mixture of 3% ethyl acetate and hexane) to obtain 0.75 g of the above-mentioned compound (yield 85%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH2:19]([NH2:22])[CH2:20][CH3:21].[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:22][CH2:19][CH2:20][CH3:21])[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCNc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1

Procedure:
A solution of (±)-cis-4-(-2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.531 g, 2.00 mmol) from Example 4 and propylamine (1.12 g, 18.19 mmol) in 8 mL of ethanol was stirred at reflux for 2 hours. The solution was allowed to cool to room temperature before the addition of 2 mL of 1.0 N NaOH. Concentration of the solution afforded the crude product which was purified by elution from a silica gel column with 5% methanolchloroform (0.46 g, 80%). Crystallization of such a sample from ethanol-ethyl acetate yielded a white powder, m.p. 138-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:21])[F:22])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
130 mg (purity 93%, 0.35 mmol) of 2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, water/methanol gradient). Yield: 104 mg (56% of theory)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=2)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]=[C:6]3[CH2:8][CH2:9][CH2:10][C:5]3=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=3)[CH:3]=2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(Cl)nc3c2CCC3)cc1
Reactant: C1COCCN1
Product: CCOC(=O)Cc1ccc(Nc2cc(N3CCOCC3)nc3c2CCC3)cc1
Yield: 24.8 %

Procedure:
Following general procedure B1, ethyl 2-(4-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.120 g, 0.36 mmol) was reacted with morpholine (0.063 g, 0.73 mmol) to afford the title compound (0.034 g, 15%) as an orange foam. MW=381.47. APCI MS m/z 382 [M+H]+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[C:12]([F:21])=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[CH:18][CH:17]=[CH:16]4)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1>[F:21][C:12]1[C:11]([N:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1
Reactant: Fc1ccc2cccnc2c1N1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1CCN(c2c(F)ccc3cccnc23)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a solution of 8-(1.4-dioxa-8-azaspiro[4.5]dec-8-yl)-7-fluoroquinoline (Step 2, 1.73 g) in tetrahydrofuran (50 mL) was added aq. 2N aqueous HCl (10 mL). The resulting mixture was stirred at 50° C. for 3 hours. The reaction mixture was then cooled to room temperature, poured into 2.5 N aqueous NaOH and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give 1.17 g of the desired product as a yellow oil; MS (ES) m/z (relative intensity): 245 (M+H)+ (100).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([O:27][C:28](=[O:30])[CH3:29])[CH:8]=[CH:9][C:10]=1[C:11]1[C:12](=[O:26])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][C:23](=[O:25])[CH3:24])[CH:15]=2)(=[O:3])[CH3:2].[Br:31]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.[W]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([O:27][C:28](=[O:30])[CH3:29])[CH:8]=[CH:9][C:10]=1[C:11]1[C:12](=[O:26])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][Br:31])=[CH:18][CH:17]=[C:16]([O:22][C:23](=[O:25])[CH3:24])[CH:15]=2)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc(-c2c(C)c3ccc(OC(C)=O)cc3oc2=O)c(OC(C)=O)c1
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc(-c2c(CBr)c3ccc(OC(C)=O)cc3oc2=O)c(OC(C)=O)c1

Procedure:
A mixture of acetic acid 3-acetoxy-4-(7-acetoxy-4-methyl-2-oxo-2H-chromen-3-yl)-phenyl ester (0.767 g, 1.87 mmol, 1 eq), N-bromosuccinimide (0.349 g, 1.962 mmol, 1.05 eq) and benzoyl peroxide (0.035 g, 0.145 mmol) in carbon tetrachloride (30 mL) was stirred and heated to reflux under nitrogen in presence of a 100W tungsten lamp for 20 hours. Reaction monitoring by MS and TLC showed the presence unreacted starting material, and additional N-bromosuccinimide (0.060 g, 0.34 mmol) and benzoyl peroxide (0.008 g) were added to the reaction mixture and the reaction was heated at reflux under nitrogen for an additional 2 hours. The mixture was evaporated to dryness, dissolved in hot dichloromethane and purified by column chromatography on silica gel using 3% ethyl acetate/hexane as an eluent to yield the title product as a tan crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16][C:17]([NH:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.Cl.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16][CH2:17][NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)Cc2cc(Br)ccc2OCc2ccccc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NCCc2cc(Br)ccc2OCc2ccccc2)cc1
Yield: 57.7 %

Procedure:
A mixture of ethyl 4-[2-benzyloxy-5-bromophenylacetamido]-benzoate (2.5 g) and BH3. THF (10 mM) in THF (60 ml) was stirred at 50° C. for 2 hours, cooled (ice bath) and diluted with 2N HCl solution (10 ml) and diethyl ether (50 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel eluting with dichloromethane to give ethyl 4-[N-(2-benzyloxy-5-bromophenethyl)amino]benzoate (1.4 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH3:32][O:33][CH2:34][C:35]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:36]
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCNCC3)c[nH]c12
Reactant: COCC(=O)Cl
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCN(C(=O)COC)CC3)c[nH]c12

Procedure:
Starting from 4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A184) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: S(Cl)(Cl)=[O:2].[Br:5][C:6]1[NH:7][C:8]2[CH2:9][CH2:10][CH2:11][C:12](=[N:15]O)[C:13]=2[CH:14]=1>C1COCC1.CCOC(C)=O>[Br:5][C:6]1[NH:7][C:8]2[CH2:9][CH2:10][CH2:11][NH:15][C:12](=[O:2])[C:13]=2[CH:14]=1
Reactant: ON=C1CCCc2[nH]c(Br)cc21
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NCCCc2[nH]c(Br)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.3 %

Procedure:
Thionyl chloride (0.06 mL, 0.90 mmol) was added to a solution of 2-bromo-6,7-dihydro-1H-indol-4(5H)-one oxime (305a) (186 mg, 0.81 mmol) in THF (8.0 mL) at 25° C., and the resulting solution was stirred at 25° C. for 18 h. The reaction mixture was then diluted with EtOAc (40 mL), sequentially washed with saturated aq. NaHCO3 (2×30 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% MeOH/DCM) furnished 2-bromo-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one (102 mg, 0.44 mmol, 55% yield) as a light-brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (1H, br. s.), 7.36 (1H, t, J=4.5 Hz), 6.27 (1H, d, J=2.7 Hz), 3.09-3.16 (2H, m), 2.82 (2H, t, J=6.6 Hz), 1.82-1.91 (2H, m). m/z (ESI, +ve) 228.9/231.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([N+:24]([O-])=O)[CH:3]=1.C(O)(=O)C>C(O)C.[Fe]>[NH2:24][C:4]1[CH:3]=[C:2]([Br:1])[CH:23]=[CH:22][C:5]=1[C:6]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:7]
Reactant: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(Br)ccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Yield: 106.6 %

Procedure:
0.42 g (0.001 mol) of 1-benzyl-piperidin-4-yl 4-bromo-2-nitro-benzoate was dissolved in 6 ml of ethanol and treated with 6 ml of glacial acetic acid and 0.225 g (0.004 mol) of iron powder. The mixture was boiled at reflux for 6 hrs. and concentrated and the residue was made basic with sat. sodium carbonate solution. The aqueous phase was extracted with ethyl acetate and the organic phase was washed with sat. sodium chloride solution and dried over sodium sulfate. After concentration the residue was chromatographed on silica gel with ethyl acetate/hexane (1:4). 0.415 g (100%) of 1-benzyl-piperidin-4-yl 2-amino-4-bromo-benzoate was obtained as white crystals.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH:4]([NH:25][C:26](=[O:42])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[N:34]1[CH2:39][CH:38]([CH3:40])[CH2:37][CH:36]([CH3:41])[CH2:35]1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1>[Cl:33][C:31]1[CH:30]=[CH:29][C:28]([N:34]2[CH2:39][CH:38]([CH3:40])[CH2:37][CH:36]([CH3:41])[CH2:35]2)=[C:27]([CH:32]=1)[C:26]([NH:25][CH:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:11]=1)[C:3]([OH:43])=[O:2])=[O:42]
Reactant: COC(=O)C(Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1N1CC(C)CC(C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1CC(C)CN(c2ccc(Cl)cc2C(=O)NC(Cc2ccc(-c3ccccc3Oc3ccccc3)cc2)C(=O)O)C1
Yield: 93.4 %

Procedure:
A solution of 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoic acid (0.250 g, 0.933 mmol) in DMF (4.0 mL) was reacted with (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (0.360 g, 0.933 mmol), HBTU (0.355 g, 0.933 mmol), and DIEA (0.500 mL, 2.800 mmol) by the general procedure A. The crude product was purified by flash column chromatography on silica gel using DCM (+20% hexane) to give 0.435 g (62%) of 2-[5-Chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester. A solution of this ester (0.200 g, 0.334 mmol) in THF (4.0 mL) was reacted with LiOH (0.050 g, 1.172 mmol) by the general procedure I to give 0.182 g (93%) of 2-[5-Chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid as a white solid. LCMS: 584 (M+1)+. 1H NMR (CDCl3) 11.20 [d, 1H], 8.21 [d, 1H], 7.45 [m, 2H], 7.39 [m, 2H], 7.23 [m, 8H], 7.02 [m, 2H], 6.86 [m, 2H], 4.90 [m, 1H], 3.38 [dd, 5.60 Hz, 1H], 3.26 [dd, 1H], 2.80 [m, 2H], 2.16 [t, 1H], 2.04 [t, 1H], 1.70 [m, 2H], 1.43 [m, 1H], 0.76 [m, 6H], 0.58 [m, 1H].
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:32]#[C:33][CH2:34][O:35][CH3:36])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>[Pt]=O>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(C#CCOC)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Agent: O=[Pt]
Product: CCCCCCc1cccc(-c2nc(CCCOC)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 14, [2-(3-hexyl-phenyl)-5-(3-methoxy-prop-1-ynyl)-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 32) was hydrogenated using platinum oxide as catalyst to give the title compound as light yellow oil. MS: 495.4 (MH+).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:90]=[CH:91][CH:92]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C:78]#[N:79])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:90]=[CH:91][CH:92]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH2:77][C:78]#[N:79])[CH2:75][CH2:76]5)=[N:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CC#N)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#CCN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Yield: 33.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 2-(4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl) acetonitrile (60 mg, 0.092 mmol) was hydrolyzed by lithium hydroxide (8 mg, 0.185 mmol) in THF/methanol/water (5/1/1 ml) to yield 15 mg (33.3% yield) of the titled compound. 1H NMR (CDCl3, 400 MHz): δ 9.19 (s, 1H), 8.50-8.47 (dd, 2H), 8.128-8.123 (d, 1H), 7.86 (s, 1H), 7.79-7.76 (dd, 1H), 7.70 (s, 1H), 7.447-7.441 (d, 1H), 7.35-7.30 (m, 1H), 7.10-6.90 (m, 3H), 6.80-6.78 (d, 1H), 5.39 (s, 2H), 3.70-3.67 (t, 4H), 3.61 (s, 2H), 2.76-2.74 (t, 4H). MS: m/z=493.4 (M+1), HPLC: 97.07% in method A.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH:7]2[CH2:11][C:10](=[O:12])[CH:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:8]2=[O:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>ClCCl>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH:7]2[CH2:11][C:10]([O:12][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:8]2=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(C)c(C2C(=O)CC(Cc3ccc(F)cc3)C2=O)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(C2=C(OC(=O)C(C)(C)C)CC(Cc3ccc(F)cc3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of 4-(4-fluoro-benzyl)-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (30 mg, 0.09 mmol) in dichloromethane (1 ml) and triethylamine (52 μl, 0.37 mmol) is added the pivaloyl chloride (34 μl, 0.37 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 2,2-dimethyl-propionic acid 4-(4-fluoro-benzyl)-3-oxo-2-(2,4,6-trimethyl-phenyl)-cyclopent-1-enyl ester (31 mg).
Reaction SMILES: C([NH:3][CH:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:5])=O.[OH-].[Na+]>Cl>[NH2:3][CH:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:5]
Reactant: CCCCCCCCCCCC(C)NC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCC(C)N
Yield: 76 %

Procedure:
60 g of 2-formamidotridecane are refluxed in 400 ml of 2 N HCl for 6 hours. The reaction mixture is then cooled in an ice bath, made alkaline with conc. NaOH, extracted with ether, and the ethereal extract is dried over Na2SO4. The ether is distilled off and the residue is then distilled in vacuo, affording 40 g of 2-aminotridecane. Boiling point: 68°-71° C./0.05.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.CN(C)C=O.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CCOC(C)=O>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([C:23]([N:1]2[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]2)=[O:24])[CH2:21][CH2:22]1
Reactant: O=C(O)C1(c2ccc(Cl)cc2Cl)CC1
Reactant: OC1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N1CCC(O)C1)C1(c2ccc(Cl)cc2Cl)CC1
Reaction time: 0.05 h

Procedure:
To a solution of 3-pyrrolidinol (0.861 mL, 0.0106 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) were added 1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid and BOP. After the mixture was stirred for 3 min, DIEA was added. After the reaction mixture was stirred for 3 h, the solution was diluted with AcOEt, washed with sat'd. NaHCO3 aq. (×3), water and brine successively, dried with MgSO4, and concentrated in-vacuo.
Reaction SMILES: C[S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14](N)=[CH:13][CH:12]=[CH:11][N:10]=1.C1COCC1.[H+].[B-](F)(F)(F)F.N([O-])=O.[Na+]>O>[N:10]1[C:9]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[S:2][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CSc1ccccc1-c1ncccc1N
Agent: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)sc1cccnc12
Temperature: -10 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
The 500 mL round-bottom flask, equipped with magnetic stirrer and reflux condenser was charged with 2-(2-(methylthio)phenyl)pyridin-3-amine (8.42 g, 39 mmol), 70 mL THF, 70 mL HBF4 (50% in water) and 40 mL H2O. Reaction mixture was cooled to −10° C., and solution of sodium nitrite (5.6 g in 20 mL water) was added dropwise. Reaction mixture was warmed gradually to room temperature and stirred overnight. The reaction mixture was diluted with 500 mL of water and extracted with ethyl acetate (4×50 mL). Organic fractions were combined, dried over sodium sulfate and evaporated, the residue was subjected to column chromatography on silica gel with hexane/ethyl acetate 9/1 mixture, providing aza-dibenzothiophene (3.5 g, colorless needles from hexane/ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.[CH2:11]=[CH:12][CH:13]=[CH2:14]>>[CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]2[CH:6]([C:7](=[O:9])[CH:8]=1)[CH2:14][CH:13]=[CH:12][CH2:11]2
Reactant: C=CC=C
Reactant: COC1=CC(=O)C=CC1=O
Product: COC1=CC(=O)C2CC=CCC2C1=O

Procedure:
Little is known, however, concerning the reaction of methoxy and 2,6-dimethoxy-p-benzoquinone. (The latter can be generated from lignin). It has been shown that methoxy-p-benzoquinone will react with 1,3-butadiene to give 2-methoxy-4a,5,8,8a-tetrahydronapthoquinone [G. I. Birnbaum, J. Org. Chem., 25, 1660-1, (1960)]and with 2,3-dimethyl-1,3-butadiene to give 5,8-dihydro-2-methoxy-6,7-dimethyl -1,4-napthoquinone [M. F. Ansell, J. Chem. Soc., 3020, (1963)]. A more recent publication has shown that 2,6-dimethoxy-p-benzoquinone can be combined with isoprene to give a mixture of 2-methoxy-6-methyl-1,4-napthoquinone and 2-methoxy-7-methyl-1,4-napthoquinone [I.-M. TegmoLarsson, Tetra. Letters, 22, 2043-6, (1981)].