Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3CC[C@H](CCCCC)C[CH2:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)C.S([O-])(O)(=O)=O.[K+].[C:33]1([CH3:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CCOCC>[CH2:39]([C@H:33]1[CH2:38][CH2:37][C@H:36]([CH:17]=[CH:16][C:13]2[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)[CH2:35][CH2:34]1)[CH2:9][CH2:4][CH2:5][CH3:6]
Reactant: Cc1ccccc1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(C)O)cc3)cc2)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Product: CCCCC[C@H]1CC[C@H](C=Cc2ccc(-c3ccccc3)cc2)CC1

Procedure:
First, 9.39 g of 4-(1-hydroxyethyl)-4′-(trans-4-pentylcyclohexyl)biphenyl, 0.52 g of potassium hydrogensulfate, and 50 ml of toluene were put in a 300 ml flask provided with a water content quantitative tube, and subjected to azeotropic dehydration under reflux for four hours. After the reaction, ether was added to the reaction solution, which was then washed with a saturated brine, and dried with sodium sulfate. The solvent was then distilled off. The residue was recrystallized from hexane to obtain 1.88 g (Y: 21.1%) of 4-(trans-4-pentylcyclohexyl)vinylbiphenyl. The purity of the resultant compound was 100.0% as measured by GC, 99.9% as measured by HPLC, and 1 spot as measured by TLC. The phase transfer temperature of the resultant compound was as follows.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=2C=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:43][C:44]([O:46][CH3:47])=[O:45])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:48]O>>[CH3:48][C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)=[CH:16][C:17]=1[CH:21]=[CH:43][C:44]([O:46][CH3:47])=[O:45]
Reactant: Cc1cccc(NC2CCN(Cc3ccccc3)CC2)c1C=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CO
Product: COC(=O)C=Cc1cc(NC2CCN(Cc3ccccc3)CC2)ccc1C

Procedure:
To N-(1-benzyl-4-piperidinyl)-2-formyl-3-methylaniline (7.0 g) are added methanol (100 ml) and methyl (triphenylphosphoranylidene)acetate (15 g) and the mixture is refluxed for 1 hour. After cooling, the formed crystals are separated by filtration to give methyl 2-methyl-5-[(1-benzyl-4-piperidinyl)amino]cinnamate (5.6 g) as pale yellow powders, m.p. 140°-142° C.
Reaction SMILES: [N:1]([CH:4]([C:14]1[C:15]([O:25][CH2:26][CH3:27])=[C:16]([C:22](=[O:24])[CH3:23])[CH:17]=[C:18]([Cl:21])[C:19]=1[F:20])[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.[Cl-].[Na+].O>[NH2:1][CH:4]([C:14]1[C:15]([O:25][CH2:26][CH3:27])=[C:16]([C:22](=[O:24])[CH3:23])[CH:17]=[C:18]([Cl:21])[C:19]=1[F:20])[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(CO[Si](C)(C)C(C)(C)C)N=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(N)CO[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Yield: 99.7 %

Procedure:
1-[3-(1-Azido-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-chloro-2-ethoxy-4-fluorophenyl]ethanone (750 mg, 1.8 mmol) (from Step 5) was stirred in tetrahydrofuran (10 mL) with water (0.33 mL) and triphenylphosphine was added. The mixture was heated to 60° C. for 2 hours and cooled to rt. Brine was added and the mixture was extracted with ethyl acetate. The extracts were dried over sodium sulfate, filtered and evaporated to give the desired compound 700 mg, 100%. LCMS calculated for C18H30ClFNO3Si (M+H)+: m/z=390.2; found: 390.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([NH2:27])=[O:26].CO.C(Cl)Cl>CC1C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[C:5]([Cl:20])=[CH:4][N:3]=[C:2]([NH:21][C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:25]([NH2:27])=[O:26])[N:7]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)Nc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Cc1ccc(C(N)=O)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CC(=O)Nc1ccccc1Nc1nc(Nc2cc(C(N)=O)ccc2C)ncc1Cl
Yield: 31.4 %

Procedure:
A solution of Intermediate 1 (1 g, 3.24 mmol) and 3-amino-4-methylbenzamide (584 mg, 3.89 mmol) in 0.08 M PTSA in 1,4-dioxane was heated to 90° C. for 48 h. TLC showed the completion of starting material (TLC system: 10% methanol/DCM, (Rf): 0.5). The reaction mixture was concentrated, quenched with water, and the precipitated solid was filtered and dried under vacuum. The crude solid was purified by silica gel column chromatography by using 3% methanol/DCM as eluents. The purified solid was further triturated with ether, filtered and dried under vacuum to get the title compound as an off-white solid (430 mg, 31%). 1HNMR (400 MHz, D6-DMSO) δ 2.17 (s, 3H), 5.78-5.81 (dd, 1H J=1.8, 10.1 Hz), 6.28-6.32 (dd, 1H J=1.8, 17 Hz), 6.43-6.50 (dd, 1H J=10.1, 17 Hz), 7.04-7.08 (m, 2H), 7.18-7.24 (m, 2H), 7.27 (br s, 1H), 7.52-7.54 (dd, 1H J=1.7, 7.9 Hz), 7.73-7.76 (m, 1H), 7.87 (br s, 1H), 7.92 (d, 1H), 8.03 (s, 1H), 8.39 (s, 1H), 8.62 (s, 1H), 10.19 (s, 1H). MS m/z: 423.5 (ES+, M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.C([Li])CCC.[C:20]1(=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCCCCC.C(OCC)(=O)C>CCOCC>[OH:26][C:20]1([C:6]2[CH:7]=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[O:4][CH2:3][O:2][CH3:1])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCCC1
Reactant: COCOc1cccc2ccccc12
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COCOc1c(C2(O)CCCCC2)ccc2ccccc12
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
A solution of 1-methoxymethoxy-naphthalene (3.76 g, 0.020 mole) in dry ether (40 mL) was treated with n-butyllithium (1.6M in hexane; 25.0 mL, 0.040 mole) at room temperature over a period of 15 minutes. After stirring for an additional 1.5 hours, a solution of cyclohexanone (4.90 g, 0.050 mole) in ether (15 mL) was added and the resulting mixture was stirred at room temperature for 2 hours. It was then quenched with saturated aqueous ammonium chloride and the crude product was isolated by extraction with ether. Chromatography with 9:1 hexane/ethyl acetate provided the title compound as a colorless oil (3.30 g, 58%).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4](=[O:13])[CH2:5][C@@H:6]([CH2:10][CH:11]=[CH2:12])[C:7]([OH:9])=O.O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:28]([O:30][C:31](=[O:36])[C@H:32]([CH2:34][OH:35])[NH2:33])[CH3:29].C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:14][C:2]([CH3:1])([CH3:15])[CH2:3][C:4](=[O:13])[CH2:5][C@@H:6]([CH2:10][CH:11]=[CH2:12])[C:7]([NH:33][C@@H:32]([CH2:34][OH:35])[C:31]([O:30][CH2:28][CH3:29])=[O:36])=[O:9]
Reactant: C=CC[C@H](CC(=O)CC(C)(C)C)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C=CC[C@H](CC(=O)CC(C)(C)C)C(=O)N[C@@H](CO)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.8 %

Procedure:
A solution (2R)-2-(4,4-dimethyl-2-oxopentyl)-4-pentenoic acid (Preparation 112) (15.91 g, 74.3 mmol), 1-hydroxybenzotriazole hydrate (11.00 g, 81.4 mmol), L-serine ethylester hydrochloride (13.84 g, 81.6 mmol) and N,N-diisopropylethylamine (27 ml, 156.0 mmol) in dichloromethane (280 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15.67 g, 81.7 mmol) and stirred at room temperature for 18 hours under a nitrogen atmosphere. The reaction mixture was diluted with dichloromethane and washed with water, aqueous citric acid (2M), saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulphate and filtered. The solvent was removed under reduced pressure to afford the title compound as a yellow oil (23.8 g).
Reaction SMILES: O[C@@H:2]1[CH2:7][N:6](C(=O)C(F)(F)F)[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C.C(O)(=O)C>[CH2:44]([O:51][NH:52][C@H:2]1[CH2:7][NH:6][C@H:5]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:4][CH2:3]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](O)CN1C(=O)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Temperature: 0 °C
Yield: 74.2 %

Procedure:
A solution of 47.9 g (161 mmol) of (2S,5S)-tert-butyl 5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate in dehydrated acetonitrile (318 mL) was cooled from −30 to −40° C. under argon atmosphere, and 20.5 mL (177 mmol) of 2,6-lutidine was added, and then 28.4 mL (169 mmol) of trifluoromethanesulfonic acid anhydride was added dropwise over 40 minutes, followed by further allowing to react at −30° C. for 15 minutes. To this reaction mixture was added 39.7 g (322 mmol) of benzyloxyamine (washed with acetonitrile (11 mL)) within 8 minutes, followed by raising the temperature to 0° C. within 30 minutes, and further 20.5 mL (177 mmol) of 2,6-lutidine was added, followed by allowing to react at 0 to 5° C. for 2 days. This reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate (960 mL) and washed sequentially with water (960 mL), 10% aqueous citric acid solution (960 mL×3 times), 6.5% aqueous sodium hydrogencarbonate solution (480 mL) and saturated brine (480 mL). Each aqueous layer was back-extracted with ethyl acetate (960 mL), the organic layers were combined, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 1,4-dioxane (320 mL) solution and water (86 mL), and, under ice cooling, 2.5M NaOH (128 mL) was added dropwise, followed by allowing to react at the same temperature for 0.5 hours. Acetic acid (ca. 9.3 mL) was added to the reaction mixture, followed by concentration under reduced pressure, and subsequently the resulting concentrated residue was extracted with ethyl acetate (580 mL, 290 mL). After the organic layers were washed respectively with 50% aqueous potassium carbonate solution (580 mL), they were combined, and the solvent was distilled off under reduced pressure. The resulting residue was applied to silica gel column chromatography (hexane/ethyl acetate=4/1→0/1→ethyl acetate/methanol=100/1→19/1) to afford 36.58 g of the title compound as a colorless oil (yield 74%). Instrumental data were consistent with those of Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:36][CH3:37])=[C:19]([CH2:23][CH:24]4[CH2:29][CH2:28][N:27]([CH2:30][C:31]([O:33]CC)=[O:32])[CH2:26][CH2:25]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:36][CH3:37])=[C:19]([CH2:23][CH:24]4[CH2:25][CH2:26][N:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][CH2:29]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CN1CCC(Cc2cccc(-c3nsc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1c(CC2CCN(CC(=O)O)CC2)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 90 °C
Yield: 77.5 %

Procedure:
To a solution of ethyl (4-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-1-piperidinyl)acetate (D145) (80 mg, 0.148 mmol) in Isopropanol (6 mL) and Water (6.00 mL) was added NaOH (1.476 mL, 0.738 mmol). The reaction solution was heated to 90° C. for 2 hours. The solvent was removed in vacuo and the residue was acidified to pH=3-4, extracted with ethyl acetate. The combined organic phases were dried, concentrated and purified by Mass Directed AutoPrep to afford (4-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-1-piperidinyl)acetic acid (E105) (59 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 1.01 (3H, t), 1.28 (6H, d), 1.55 (2H, m), 1.72 (3H, m), 2.62 (2H, d), 2.87 (4H, m), 3.38 (2H, m), 3.98 (2H, s), 4.79 (1H, m), 7.23 (2H, m), 7.32 (1H, d), 7.59 (1H, dd), 7.95 (1H, dd), 8.07 (1H, d). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C27H32ClN3O3S requires 513.2. found 514.2 (M+H+).
Reaction SMILES: C1([N:5]2[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)CCC1.[H-].[Na+].Br[C:15]1[S:16][C:17]2[CH2:18][CH2:19][N:20]([C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:22][C:23]=2[N:24]=1.O1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:31]1([C:8]2([O:11][C:15]3[S:16][C:17]4[CH2:18][CH2:19][N:20]([C:25]([CH:27]5[CH2:29][CH2:28]5)=[O:26])[CH2:21][CH2:22][C:23]=4[N:24]=3)[CH2:7][CH2:6][NH:5][CH2:10][CH2:9]2)[CH2:34][CH2:33][CH2:32]1
Reactant: OC1CCN(C2CCC2)CC1
Reactant: O=C(C1CC1)N1CCc2nc(Br)sc2CC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: O=C(C1CC1)N1CCc2nc(OC3(C4CCC4)CCNCC3)sc2CC1

Procedure:
1-Cyclobutyl-piperidin-4-ol (0.04 grams, 0.26 mmol) in tetrahydrofuran (3 mL) was treated with cooled and stirred suspension of sodium hydride (0.021 grams, 0.51 mmol) in tetrahydrofuran (8 mL) slowly over the period of 5 minutes and the reaction mixture was stirred for 2 hours at room temperature. A solution of (2-Bromo-4,5,7,8-tetrahydro-thiazolo[5,4-d]azepin-6-yl)-cyclopropyl-methanone (0.053 grams, 0.17 mmol, obtained in above step) in tetrahydrofuran (3 mL) was added drop wise over a period of 5 minutes and refluxed for 15 hours. Reaction mass was quenched onto ice cold water and the product was extracted with ethyl acetate (3×10 mL). The combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. Organic volatiles were evaporated under vacuum. The residue obtained was purified by flash chromatography (methanol/chloroform 3/97) to obtain the title compound (0.05 grams).
Reaction SMILES: C(O[CH2:5][CH:6]=[CH2:7])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:27]([C:30]1[C:31](=[O:40])[NH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1)([O-:29])=[O:28]>C1COCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:27]([C:30]1[C:31](=[O:40])[N:32]([CH2:7][CH:6]=[CH2:5])[C:33]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: O=c1[nH]c(C(F)(F)F)ccc1[N+](=O)[O-]
Reactant: C=CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCn1c(C(F)(F)F)ccc([N+](=O)[O-])c1=O
Reaction time: 24 h
Yield: 33.8 %

Procedure:
A solution of allyl acetate (13.5 ml, 125 mmol) in THF (8 ml), was evacuated and purged with argon (3 times). Palladium acetate (122 mg, 0.50mmol) and triphenylphosphine (525 mg, 2.0 mmol) were added as solutions in tetrahydrofuran (1.5 ml each), followed by 3-nitro-6-trifluoromethyl-2-pyridinone (2.6 g, 12.5 mmol) in THF (2 ml). The reaction was heated to reflux for 64 h, and more allyl acetate (13.5 ml, 125 mmol), triphenylphosphine (525 mg, 2.0 mmol), palladium acetate (122 mg, 0.5 mmol), and tetrahydrofuran (13 ml) were added. After a further 24 h and 48 h at reflux addditional allyl acetate (13.5 ml, 125 mmol), palladium acetate (122 mg, 0.5 mmol), and triphenylphosphine (525 mg, 2.0 mmol) were added and the reaction was heated to reflux for a further 24 h. The reaction was cooled and evaported in vacuo to a gum which was purified by flash column chromatography on silica (15% ethyl acetate/hexane) to give the product contaminated with unreacted 3-nitro-6-trifluoromethyl-2-pyridinone. This material was diluted with ethyl acetate and washed with water adjusted to pH 12 with sodium carbonate, dried (Na2SO4), and evaporated in vacuo to give the title compound (1.05 g): 1H NMR (CDCl3) selected signals at δ4.80 (d, J=5.8 Hz, 2H), 5.28-5.33 (m, 2H), 5.86-5.96 (m, 1H), 6.80 (d, J=7.9 Hz, 1H), 8.22 (d, J=7.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH3:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:18]>O1CCOCC1>[ClH:1].[Cl:12][C:10]1[N:9]=[CH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:15]([CH3:14])[CH:16]=3)[C:3]=2[CH:11]=1
Reactant: Cc1cc(N)ccc1Oc1ccccc1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncnc3cnc(Cl)cc23)ccc1Oc1ccccc1
Temperature: -80 °C
Yield: 100 %

Procedure:
The 4,6-dichloro-pyrido[3,4-d]pyrimidine obtained from the previous reaction was taken up in dioxane (50 ml), the 3-methyl 4-phenoxy aniline hydrochloride (2.8 g, 12 mmol) was added and the contents heated to an external bath temperature of −80° C. for 3 hours, whereupon yellow precipitation occurred. Further dioxane (20 ml) was added and the contents heated at −75° C. for 12 hours. The solution was then filtered and the yellow solid placed under vacuum to provide the desired (6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine hydrochloride (3.6 g, ˜100%). 1H NMR (CD3OD; 400 MHz) δ 9.05 (s, 1H), 8.87 (s, 1H), 8.64 (s, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.58 (dd, J=8.7, 2.5 Hz, 1H),7.35 (dd, J=8.7, 7.5 Hz, 2H), 7.10 (t, J=7.2 Hz, 1H), 6.94 (d, J=8.7 Hz, 3H), 2.29 (s, 3H). MS m/z (MH+): 363.2
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][CH:21]=[CH:20]5)=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.CC1(C)C(C)OB([C:34]2C=N[N:37]([CH:39]3CCN(C(OC(C)(C)C)=O)C[CH2:40]3)[CH:38]=2)O1>>[NH:37]1[CH2:39][CH2:40][CH:1]([N:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([CH2:16][C:17]5[CH:18]=[C:19]6[C:24](=[CH:25][CH:26]=5)[N:23]=[CH:22][CH:21]=[CH:20]6)=[CH:14][N:15]=4)[N:12]=3)[CH:4]=[N:3]2)[CH2:34][CH2:38]1
Reactant: CC1OB(c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)OC1(C)C
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cn1
Product: c1cnc2ccc(Cc3cnc4ccc(-c5cnn(C6CCNCC6)c5)nn34)cc2c1

Procedure:
The title compound was prepared in analogy to the synthesis of compound of Example 2, using tert-butyl 4-(4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and with an additional deprotection step before final reduction (tR 1.0 min (conditions 1), MH+=410).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:22]1([O:28][CH2:29][CH3:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.CN(C)C=O>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:25]2[CH:26]=[CH:27][C:22]([O:28][CH2:29][CH3:30])=[CH:23][CH:24]=2)=[O:9])[CH:10]=1
Reactant: COc1cc(Cl)c(C(=O)O)cc1Br
Reactant: CCOc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOc1ccc(C(=O)c2cc(Br)c(OC)cc2Cl)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-chloro-4-methoxybenzoic acid (4, 15 g, 56.5 mmol) in toluene (72 mL) was added thionyl chloride (8.24 mL, 113 mmol) and N,N-dimethylformamide (0.1 mL). The solution was refluxed at 90° C. for 4 h, cooled to room temperature and evaporated to remove toluene and residual reagent. The obtained acyl chloride was diluted with dichloromethane (240 mL) and added portionwise aluminum chloride (8.3 g, 62.2 mmol) and phenetole (7.2 mL, 56.5 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight, quenched with 1N HCl (15 mL) and H2O (15 mL). The organic layer was extracted with dichloromethane two times, washed with 1N HCl and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellowish solid which was used without further purification.
Reaction SMILES: [C:1]([O:7]C)(=O)[CH2:2][C:3]([CH3:5])=O.[CH3:9][C:10](O)(C#C)[CH3:11].[C:15](=O)=O>CCC(CC([O-])=O)=O.CCC(CC([O-])=O)=O.CCC(CC([O-])=O)=O.[Al+3].C1(=O)OC(C)CO1>[CH3:9][C:10](=[CH:5][CH:3]=[CH:2][C:1](=[O:7])[CH3:15])[CH3:11]
Reactant: O=C=O
Reactant: COC(=O)CC(C)=O
Reactant: C#CC(C)(C)O
Agent: CCC(=O)CC(=O)[O-]
Agent: [Al+3]
Solvent: CC1COC(=O)O1
Product: CC(=O)C=CC=C(C)C
Temperature: 170 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A mixture of 5.3 g of the aluminum tri(methyl acetylacetate) catalyst mentioned in Example 1 and 85 g of 1,2-propylene carbonate was heated to 170° C. and, at this temperature a mixture of 55 g (0.47 mol) of methyl acetoacetate and 43.7 g (0.52 mol) of 2-methyl-3-butyn-2-ol was metered in at a constant rate over the course of 4 h. After the addition was complete, the mixture was stirred at 170° C. for 30 min. During this time, CO2 was evolved and low boilers distilled out. The reaction mixture was subsequently cooled, and the 2-methyl-2,4-heptadien-6-one which was formed was distilled out under about 100 mbar. This resulted in 42 g of pure 2-methyl-2,4-heptadien-6-one, which corresponds to a yield of 72% of theory based on reacted 2-methyl-3-butyn-2-ol.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([NH2:20])CCCCCCC>C(Cl)Cl>[C:1]1([CH2:7][S:8]([NH2:20])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCCCCCCCN
Solvent: ClCCl
Product: NS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
The synthesis of the sulfonamide containing carboxylic acid precursor corresponding to the autoinducer analog 10 was accomplished by the two step sequence described below. Accordingly, a solution of α-toluenesulfonyl chloride (10 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of octylamine (20 mmol) in CH2Cl2 (20 mL) at 0° C. The resulting mixture was subsequently stirred at room temperature for 30 min and was then extracted with H2O (3×24 mL) The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo to provide the corresponding α-toluenesulfonamide (262 mg, 93%) as a colorless solid. Subsequent oxidative degradation of the phenyl moiety within this compound via the procedure of Sharpless, et al. [e.g., cat. RuCl3 hydrate, NaIO4, H2O/CH3CN/CCl4 (vide supra)] furnished the α-sulfonamidoacetic acid corresponding to homoserine lactone 10. Accordingly, a mixture of the above a-toluenesulfonamide (1.00 mmol), CCl4 (2 mL), CH3CN (2 mL), H2O (3 mL) and NaIO4 (14.50 mmol) was vigorously stirred at room temperature and RuCl3 hydrate (5 mg) was added. The reaction mixture was vigorously stirred for a further 2 h at room temperature and then CH2Cl2 (10 mL) was added and the phases were separated. The upper aqueous phase was extracted with three portions of CH2Cl2 and the combined organic phases were dried (MgSO4) and the solvents were removed in vacuo. Recrystallization of the residue from EtOH provided the α-sulfonamidoacetic acid (181 mg, 72%) as a colorless solid.