Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=1[N+:20]([O-])=O)[C:6](OCC)=[O:7])[CH3:2]>[Pd].C(O)C>[NH2:17][C:14]1[CH:13]=[C:12]2[C:11]([C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:24])([CH3:23])[C:6](=[O:7])[NH:20]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(C)C(=O)Nc2cc(N)ccc21

Procedure:
A solution of 27 g. (0.079 mol) methyl-(2,4-dinitrophenyl)-malonic acid diethyl ester in 800 ml. ethanol is hydrogenated at ambient temperature in the presence of 1 g. 10% Pd/C. Subsequently, the catalyst is filtered off with suction and the filtrate is acidified with ethanolic hydrogen chloride solution, evaporated to dryness and the residue is crystallised out by the addition of isopropanol. Yield: 13.19 g. (71% of theory); m.p. 248° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.COCCN.[CH3:28][N:29](C)[CH:30]=O>>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[N:29]([CH3:30])[CH3:28])=[O:22]
Reactant: CN(C)C=O
Reactant: O=C(Nc1cccc2c(Cl)ccnc12)c1c(Cl)cccc1Cl
Agent: COCCN
Product: CN(C)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (130 mg) and 2-methoxyethylamine (210 mg) in dimethylformamide (1.5 ml) was heated for 5 hours at 100° C. The mixture was concentrated in vacuo, and the residue was purified by preparative thin layer chromatography to give 8-(2,6-dichlorobenzoylamino)-4-dimethylaminoquinoline (94 mg).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([S:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[O:24])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])[CH3:5].Cl.O>CO>[CH3:16][C:13]([C:11]1[CH:10]=[C:9]([S:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[OH:24])[CH:8]=[C:7]([C:4]([CH3:3])([CH3:5])[CH3:6])[CH:12]=1)([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(SC2CCCCC2=O)cc(C(C)(C)C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(S[C@H]2CCCC[C@H]2O)cc(C(C)(C)C)c1
Reaction time: 1 h

Procedure:
Sodium borohydride (0.40 g, 0.0105 mole) was added to a cold (3° C.) solution of 2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexanone (3.18 g, 0.0100 mole) in methanol (150 mL). After 1 hour, 10% hydrochloric acid (5 mL) and water (50 mL) were added. The methanol was removed by rotary evaporator and the title products were extracted into ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated to an oil. Silica gel chromatography separated the two title products. The major product (first off) was identified as the "cis" product by NMR.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:7]2[O:6][C:5]([C:3]([OH:2])=[O:4])=[CH:9][CH:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(Br)o1
Reactant: OB(O)c1ccccc1
Product: O=C(O)c1ccc(-c2ccccc2)o1

Procedure:
5-Bromo-furan-2-carboxylic acid methyl ester (5) (205 mg, 1 mmol) was coupled to phenylboronic acid (146 mg, 1.2 mmol) using Method E except that once the reaction was complete, the solvents were removed in vacuo. The crude residue was re-dissolved in EtOAc (10 ml) and 1M NaOH (20 ml) was added. The aqueous layer was extracted with EtOAc (3×10 ml), and the organic layer was discarded. The aqueous layer was acidified to pH 1 with conc. HCl, and extracted with EtOAc (3×10 ml). The combined organic layers were dried (MgSO4), filtered, and the solvent removed in vacuo to give the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:37])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][C:24]3([CH2:28][NH:29]C(=O)C(F)(F)F)[CH2:27][O:26][CH2:25]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:36])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.N.C[OH:40]>>[NH2:29][CH2:28][C:24]([NH:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:36])[CH:19]=2)[N:14]=[C:13]([N:5]2[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:2](=[O:37])(=[O:1])[CH2:3][CH2:4]2)[CH:22]=1)([CH2:25][OH:40])[CH2:27][OH:26]
Reactant: CO
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3(CNC(=O)C(F)(F)F)COC3)c2c1
Agent: N
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(CN)(CO)CO)c2c1
Yield: 25 %

Procedure:
A mixture of N-[(3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}oxetan-3-yl)methyl]-2,2,2-trifluoroacetamide (269 mg, 0.503 mmol) and a solution of ammonia in methanol (7 M, 10 mL,) was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford 58 mg of the product as a white solid (yield was 25%). MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.11-8.09 (t, J=6.4, 1.2 Hz, 1 H), 8.00-7.96 (m, 1 H), 7.86 (s, 1 H), 7.76-7.73 (m, 2 H), 7.64-7.60 (m, 2 H), 6.49 (s, 1 H), 5.33 (s, 2 H), 4.55 (s, 2 H), 3.82 (s, 2 H), 3.77-3.75 (m, 6 H), 2.49 (s, 3 H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)=O.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>O1CCCC1.C(OCC)(=O)C.[Na].[Ti]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[N:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(C(=O)c2nc3ccccc3s2)c1
Reactant: CN1CCC(N)CC1
Agent: [Ti]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=NC2CCN(C)CC2)c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (benzothiazol-2-yl)(m-tolyl)methanone (1.06 g) and 4-amino-1-methylpiperidine (0.456 g) in tetrahydrofurane (4 mL) is added titanium tetraisopropoxyde (1.42 g). The mixture is stirred at room temperature for 1 h, then polymethyl hydrosiloxane (1.2 mL) is added. The mixture is stirred for one day at room temperature, diluted with ethyl acetate (50 mL), hydrolysed with 3N sodium hydroxyde (30 mL). The organic phase is separated by decantation, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue is cristallised by trituration in diisopropyl oxyde. A second crop can be obtained form the mother liquor by chromatography over silica gel (gradiant dichloromethane/methanol from 98/2 to 95/5) to give [(benzothiazol-2-yl)(m-tolyl)methylene](1-methylpiperidin-4-yl)amine meting at 125° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([Cl:10])=[CH:8][C:7](Cl)=[N:6][C:5]=1[C:12]([F:15])([F:14])[F:13].[CH2:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH3:26])[C:20]=1B(O)O)[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([C:20]2[C:21]([CH2:25][CH3:26])=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:17][CH3:18])=[N:6][C:5]=1[C:12]([F:15])([F:14])[F:13]
Reactant: CCc1cccc(CC)c1B(O)O
Reactant: COC(=O)c1c(Cl)cc(Cl)nc1C(F)(F)F
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: [Na+]
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1-c1cc(Cl)c(C(=O)OC)c(C(F)(F)F)n1
Temperature: 25 °C

Procedure:
A mixture of 4,6-dichloro-2-trifluoromethyl-nicotinic acid methyl ester (1.0 g, 3.7 mmol), 2,6-diethyl-phenyl boronic acid (0.78 g, 4.4 mmol), sodium carbonate (2 M aqueous solution, 4.4 mL, 8.8 mmol), and Pd(PPh3)4 (206 mg, 0.18 mmol) is refluxed in toluene for 48 hours and then cooled to room temperature. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×50 mL). The combined organic layers are dried and the solvent removed. The crude product is purified by flash column (hexanes/ethyl acetate 8:1) to give 4-chloro-6-(2,6-diethylphenyl)-2-trifluoromethyl-nicotinic acid methyl ester as a white solid. 1H NMR: (CDCl3) 7.58 (s, 1H), 7.25 (t, 1H), 7.20 (d, 2H), 4.02 (s, 2.28 (q, 4H), 1.04 (t, 6H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23](Br)[O:22][C:18]=2[N:19]=[CH:20][N:21]=1.[CH2:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O)[CH3:36]>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH2:35][CH3:36])[O:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: CCc1ccccc1B(O)O
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1ccccc1-c1oc2ncnc(NCCCCCC(=O)OC)c2c1-c1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Add 0.50 ml of 2 M aqueous sodium carbonate solution to a mixture of 224 mg (0.50 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 18 mg (0.03 mmol) bis(triphenylphosphine)palladium(II) chloride in 11.2 ml DMSO. Next, add 187 mg (1.25 mmol) (2-ethylphenyl)boronic acid and stir the mixture for 15 h at 80° C. Filter the reaction mixture and purify directly by preparative RP-HPLC (gradient: water/acetonitrile). 69 mg (29% of theor.) of the desired product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.[ClH:33]>C(O)(C)C.C1(C)C=CC=CC=1>[ClH:33].[CH2:14]([NH:21][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: NCc1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: COc1ccc2c(c1)CC(NCc1ccccc1)CC2
Temperature: 25 °C

Procedure:
A mixture of 8 g of 7-methoxy-2-tetralone, 4.8 g of benzylamine, 150 ml of anhydrous toluene and 100 mg of p.toluenesulfonic acid is refluxed for three hours. The mixture is evaporated to dryness, the oily residue is taken up with 100 ml of methanol and to the solution thus obtained 8.5 g of sodium borohydride are cautiously added at 0°-5° C. The mixture is left under stirring at room temperature for a night, then added with 50 ml of water and left under stirring for 30 minutes. The solvent is evapored, the residue is taken up with 30 ml of water and 10 ml of a concentrated solution of ammonium hydroxide. After extraction with 200 ml of ethyl acetate, the organic phase is dried over sodium sulfate, filtered and evaporated to dryness. A dark coloured oil is obtained, which is purified by flash chromatography using a mixture ethyl acetate/methanol 95/5 as an eluent. The base so obtained is converted into its hydrochloride by solution in 40 ml of isopropanol and addition of isopropanol saturated with hydrogen chloride to give 11.4 g of 2-benzylamino-7-methoxytetraline hydrochloride; m.p. 265°-267° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Cl[C:12]1[C:13]2[CH:21]=[CH:20][N:19]=[CH:18][C:14]=2[N:15]=[CH:16][N:17]=1>>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:12]3[C:13]4[CH:21]=[CH:20][N:19]=[CH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Clc1ncnc2cnccc12
Reactant: Nc1ccc2[nH]ncc2c1
Product: c1cc2c(Nc3ccc4[nH]ncc4c3)ncnc2cn1
Yield: 96 %

Procedure:
This product was prepared in 96% yield from 5-aminoindazole (1.1 eq.) and 4-chloropyrido[3,4-d]pyrimidine (1 eq.). MP 258° C.; LC-MS: 263 (MH+).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:10][C:11]([OH:13])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:14][NH:15][C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([O:31]CCC)=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>>[N:1]1[CH:2]=[C:3]([CH2:10][C:11]([N:15]([CH3:14])[C@H:16]2[CH2:35][N:20]3[C:21]4[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]3[CH2:18][CH2:17]2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:13])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)Cc1cnc2ccccn12
Product: CN(C(=O)Cc1cnc2ccccn12)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from imidazo[1,2-a]pyridin-3-ylacetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 417.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].Cl.[NH2:20][OH:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:20][OH:21])=[O:13]
Reactant: NO
Reactant: O=C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Agent: Cl
Product: O=C(NO)c1ccccc1Nc1c(Cl)cccc1Cl
Yield: 67.2 %

Procedure:
According to the procedure of Example 1, 2-[(2,6-dichlorophenyl)amino]benzoic acid (J. S. Kaltenbronn, et al., Arzneimittel-Forschung/ Drug Research, 33(1), 4a, 621-627 (1983)) (4.1 g) is reacted with hydroxylamine hydrochloride (4.04 g) to provide 2-[(2,6-dichlorophenyl)amino]-N-hydroxybenzamide (2.9 g, 67%); mp 171-173° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH2:3]1.Cl>C(O)C.O.[Fe]>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc([N+](=O)[O-])c1)N2
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Yield: 50.1 %

Procedure:
To a stirred solution of 4,4,6-Trimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline (10 g) in Ethanol/water (150 mL/30 mL) was added concentrated hydrochloric acid (2 mL) and Iron Powder (20 g, 356 mmol). The resultant mixture was heated to reflux for 2 h. Iron Powder was filtered, and washed with ethanol. The combined filtrate was concentrated, and diluted with water. The mixture was extracted with ethyl acetate (250 mL×3). The combined organic layers were washed with saturated brine, and the brine was extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, concentrated. The residue was treated with ether and hexane to afford 4.5 g of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine as brown solid (Yield: 50%).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:18][CH2:19][C:20]1([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CN(C)C=O>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:16])[C:2]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][C:20]2([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][CH2:11]1
Reactant: Cc1cc(C)c(NC2CCNCC2)c(C)c1
Reactant: COC(=O)CC1(CCBr)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)CC1(CCN2CCC(Nc3c(C)cc(C)cc3C)CC2)CCCCC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 52.7 %

Procedure:
A suspension of 4-(mesitylamino)piperidine (250 mg, 1.15 mmol), methyl [1-(2-bromoethyl)cyclohexyl]acetate (371 mg, 1.38 mmol) and potassium carbonate (318 mg, 2.3 mmol) in N,N-dimethylformamide (3 mL) was stirred at 80° C. for 10 hours. Chloroform (10 mL) was added to the reaction mixture, the insoluble portion was filtered out, and the filtrate was concentrated under reduced pressure. The residue was dissolved in xylene (10 mL) and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (10 g Merck Art 9385, hexane:ethyl acetate=7:3-chloroform:methanol=10:1) to obtain the title compound as a brown oil (243 mg) (53% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:7]=[C:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C/C(/[O-])=C/C(C)=[O:15]>>[CH3:1][C:2]1([CH3:10])[CH2:3][C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[C:7]1=[O:15]
Reactant: CC(=O)/C=C(/C)[O-]
Reactant: CC1=CC(C)(C)CC(=O)C1
Product: CC1=CC(=O)CC(C)(C)C1=O

Procedure:
A mixture of 1380 g of a product obtained according to the hereinabove given process (β-phorone content: 51.6%) and 7 g of cobaltIII -acetylacetonate (Wacker Chemie GmbH, Munich, West Germany) was heated to about 50° under vigorous stirring (turbine speed: 1000 t/min). Air was then added to the said mixture at an initial flow of about 100-150 l/h, this flow being then progressively increased to about 300 l/h.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@@H:4]1[C:6]([CH3:8])([CH3:7])[C@@H:5]1[C:9]([OH:11])=[O:10].B(Br)(Br)Br>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of (+)-cis chrysanthemic acid (2.0 g) in toluene (18 ml) was added a solution of boron tribromide (13 mg) in toluene (2.2 ml) at room temperature under a nitrogen atmosphere. Irradiation with a high pressure mercury lamp (100 W) was made for 10 minutes under stirring. After the reaction was over, similar after-treatment as in Example 1 was applied to obtain chrysanthemic acid (1.98 g). The optical isomer ratio of the product was (+)-cis, 3.5%; (-)-cis, 3.2%; (+)-trans, 46.5%; and (-)-trans, 46.8%.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].[CH2:14]1[CH2:24][CH2:23]N2C(=NCCC2)C[CH2:15]1.C1(CBr)CC1.O>O1CCCC1>[CH:14]1([CH2:15][O:12][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[CH2:23][CH2:24]1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: C1CCC2=NCCCN2CC1
Agent: BrCC1CC1
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 77.5 °C

Procedure:
4-Difluoromethoxy 3-hydroxy benzaldehyde in tetrahydrofuran (5 vol with respect to 4-Difluoromethoxy 3-hydroxy benzaldehyde) was taken in a vessel and DBU (1.5 eq respect to 4-Difluoromethoxy 3-hydroxy benzaldehyde) was added. To this first lot of cyclopropylmethylbromide (1.5 eq respect to 4-Difluoromethoxy 3-hydroxy benzaldehyde) was added and heated to 75-80° C. After 2 hours second lot of cyclopropylmethyl bromide (0.5 eq with respect to 4-Difluoromethoxy 3-hydroxy benzaldehyde) was added and maintained at 75-80° C. for 2 hours. To this third lot of cyclopropylmethyl bromide (0.5 eq with respect to 4-Difluoromethoxy 3-hydroxy benzaldehyde) was added and maintained for 2 hours. The reaction mass was cooled to 20-25° C. and water was added. The reaction mixture was extracted with EtOAc and EtOAc extracts were washed with water. EtOAc was distilled out under reduced pressure at 40° C. to get 3-cyclopropylmethoxy 4-Difluoromethoxy benzaldehyde as brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:18][N:17]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:63]1([CH2:68][C@H:69]2[NH:72][C:71](=[O:73])[C@H:70]2[NH2:74])[CH:67]=[N:66][CH:65]=[N:64]1>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[N:63]1([CH2:68][C@@H:69]2[C@H:70]([NH:74][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:8])([CH3:9])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:29])/[C:16]3[N:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[S:18][N:17]=3)[C:71](=[O:73])[NH:72]2)[CH:67]=[N:66][CH:65]=[N:64]1
Reactant: N[C@@H]1C(=O)N[C@@H]1Cn1cncn1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)ns1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2cncn2)ns1
Reaction time: 0.33 h
Yield: 57.7 %

Procedure:
To a slurry of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)acetic acid (129 mg, 0.299 mmol) in DCM:DMF (1:1, 3 mL) at 0° C. was added DIPEA (157 μL, 0.897 mmol) followed by HATU (136 mg, 0.359 mmol). To the resulting solution, after 20 min, was added a solution of (3S,4R)-4-((1H-1,2,4-triazol-1-yl)methyl)-3-aminoazetidin-2-one (50 mg, 0.299 mmol) in DCM. After 2 h of stirring it was concentrated in vacuo and taken up in EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM) to afford the title compound (100 mg, 58%). LCMS: Rt=0.82 min, m/z=580.2 (M+1) Method 2m_acidic.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:6](I)[N:5]=[C:4]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[CH3:2].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH2:1]([N:3]1[C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:6]([C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)[N:5]=[C:4]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CCn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: CCn1c(-c2cccc(C(F)(F)F)c2)nc(-c2ccncc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [3-ethyl-5-iodo-2-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 69) was reacted with pyridine-4-yl-boronic acid to give the title compound as light yellow solid. MS: 498.1 (MH+).