Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.C(N(CC)CC)C.[Cl:18][C:19]([Cl:23])([Cl:22])[S:20]Cl>C1C=CC=CC=1>[Cl:18][C:19]([Cl:23])([Cl:22])[S:20][NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1
Reactant: ClSC(Cl)(Cl)Cl
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: ClC(Cl)(Cl)SNc1nc(C(Cl)(Cl)Cl)ns1
Yield: 23.9 %

Procedure:
To a 3-neck flask equipped with condenser, thermometer, and stirring bar was added 11.7 g (0.05 mole) 5-amino-3trichloromethyl-1,2,4-thiadiazole, 5.1 g (0.05 mole) triethylamine and 150 milliliters of benzene. After 9.3 g (0.05 mole) trichloromethane-sulfenyl chloride was added, the reaction mixture was heated at reflux for 16 hours and filtered hot. The filtrate was evaporatd under vacuum to give an orange paste which was triturated with acetonitrile, filered and washed with petroleum ether to obtain 4.4 g (24% yield) of product; mp=180° C.
Reaction SMILES: [C:1]1([P:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[CH2:12][C:11](=[O:13])[O:10][C:9]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:27]>>[C:21]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:8]([CH2:12][C:11]([OH:10])=[O:13])[C:9]([OH:14])=[O:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O
Reactant: O=C1CC(=P(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O1
Product: O=C(O)CC(C(=O)O)=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by stirring 3-triphenylphosphoranylidene dihydro-2,5-furandione (5.0 g, 0.014 mole) for 48 hours in 100 ml water. The solid residue was isolated by filtration and air-dried to give essentially quantitative yields of a product as a white crystalline solid whose IR spectrum and elemental analysis corresponded to the structure ##STR8##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[C:6]([OH:8])[CH:7]=1.[C:13]1(=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[O:14]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:9]([C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:13](=[O:14])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:22])=[CH:7][C:6]=1[OH:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(N)cc1O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(N2C(=O)c3ccccc3C2=O)cc1O
Temperature: 110 °C
Reaction time: 13 h
Yield: 83.7 %

Procedure:
A mixture of 5-amino-2-tert-butyl-phenol (300 mg, 1.82 mmol), isobenzofuran-1,3-dione (283 mg, 1.91 mmol), triethylamine (759 μL, 5.45 mmol) in toluene (5.0 mL) was stirred at 110° C. for 13 h. The reaction mixture was cooled, diluted with ethyl acetate (15 mL), and washed with 10% aqueous NaHCO3(10 mL) and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to provide 2-(4-tert-butyl-3-hydroxyphenyl)isoindoline-1,3-dione (450 mg, 84% yield) as a light brown solid which was used for next reaction without further purification. 1H NMR (400.0 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.96 (m, 2H), 7.90 (m, 2H), 7.25 (d, J=8.3 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 6.79 (dd, J=2.1, 8.3 Hz, 1H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:3][CH2:4][CH2:5][C:6](O)=[O:7].S(Cl)([Cl:27])=O>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:3][CH2:4][CH2:5][C:6]([Cl:27])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCC(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCC(=O)Cl
Yield: 99.6 %

Procedure:
Under a nitrogen atmosphere, one drop of pyridine was added to 10 g of 5,9,13,17-tetramethyloctadecanoic acid and 20 ml of methylene chloride, and 5.2 g of thionyl chloride was added dropwise thereto at room temperature. After the completion of dropwise addition, the mixture was refluxed for 1 hour and concentrated under reduced pressure to obtain 10.5 g of 5,9,13,17-tetramethyloctadecanoic acid chloride.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:23][C@@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1.Cl.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C1COCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:23][C@@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 48 %

Procedure:
0.60 g (2 mmol) of Z-Phe-OH, 0.51 g (2 mmol) of H-D-Trp-OMe.HCl, 0.46 g (2.4 mmol) of EDCI, 0.32 g (2.4 mmol) of HOBT and 0.44 ml (4 mmol) of NMM are dissolved at -10° C. in 10 ml THF and stirred at room temperature for 15 hours. The THF is distilled off under vacuum, the residue dissolved in 50 ml ethyl acetate and the organic phase washed three times with 10 ml 0.5 N HCl, 10% NaHCO3 solution and water respectively. The organic phase is dried with MgSO4 and the solvent distilled off under vacuum. 0.48 g (48%) of thin-layer chromatographically identical Z-Phe-D-Trp-OMe are obtained as a colourless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15][OH:16])[CH:5]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15][O:16][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)[CH:5]=1
Reactant: C1=COCCC1
Reactant: COC(=O)c1cccc(-c2ncsc2CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2ncsc2COC2CCCCO2)c1

Procedure:
3-(5-Hydroxymethyl-thiazol-4-yl)-benzoic acid methyl ester (1.25 g), dihydropyrane (0.84 mL) and p-toluenesulfonic acid hydrate (0.10 g) in AcOEt (12 mL) was stirred at 20° C. for 3 h. The solution was diluted AcOEt, washed with 5% NaHCO3 solution and with brine, dried and evaporated. The residual oil was purified by chromatography on silica gel using AcOEt/hexane (1:3) as eluent to give 3-[5-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-benzoic acid methyl ester (1.60 g) as a pale-yellow oil.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[CH:3]=[CH:2]1>O1CCCC1>[C:4]1(=[O:5])[O:6][CH2:1][CH2:2][CH2:3]1.[CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5]
Reactant: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Product: O=C1CCCO1
Product: OCCCCO

Procedure:
The maleic anhydride obtained can be further processed to give γ-butyrolactone, tetrahydrofuran, 1,4-butanediol or mixtures thereof, for example by direct hydrogenation of maleic anhydride in the gas phase as described in WO 97/43234 or by hydrogenation of a maleic diester in the gas phase as described in WO 97/43242.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:20](C2C=CC=CC=2)[C:21]([C:23]2(C(N)=O)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15](O)=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS([O:39][CH2:40][CH2:41][C:42]1([O:45][C:46](=[O:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:44][CH2:43]1)(=O)=O.[C:54]([O-:57])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:46]([O:45][C:42]1([CH2:41][CH2:40][O:39][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:20][C:21]([C:23]5([C:54](=[O:57])[NH:12][C:13]6[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=6)[CH2:24][CH2:25]5)=[O:22])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:44][CH2:43]1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CS(=O)(=O)OCCC1(OC(=O)c2ccccc2)CC1
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OC1(CCOc2ccc3c(Oc4ccc(NC(=O)C5(C(=O)Nc6ccccc6)CC5)cc4F)ccnc3c2)CC1)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 116.2 %

Procedure:
To a mixture of N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-N-phenylcyclo-propane-1,1-dicarboxamide (91 mg, 0.2 mmol) and 2-(1-(benzoyloxy)cyclopropyl)ethyl methanesulfonate (113.6 mg, 0.4 mmol) in DMF (3 mL) were added Cs2CO3 (195 mg, 0.6 mmol, Aladdin). The reaction was stirred at 50° C. overnight. The solvent was then removed in vacuo, and the residue was extracted with CHCl3 (30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to afford the title compound as a light yellow solid (75 mg, 58%).
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:28])[CH2:12][O:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=2)=[N:9]1.O>O1CCCC1>[CH3:7][C:8]1([CH3:28])[CH2:12][O:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[CH:23][CH:24]=2)=[N:9]1
Reactant: CC1(C)COC(c2ccccc2-c2ccc(C(=O)O)cc2)=N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Reaction time: 2 h
Yield: 88.3 %

Procedure:
1.28 g (33.7 mmol) of aluminum lithium hydride was suspended in tetrahydrofuran (20 ml). At room temperature, 5.0 g (16.9 mmol) of 4,4-dimethyl-2-(4'-carboxybiphenyl-2-yl)oxazoline was gradually added thereto, followed by stirring for 2 hours. After the reaction liquid was cooled with ice, 100 ml of water was added thereto to conduct hydrolysis, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 4.2 g of the title compound (yield 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:11]([Mg]Cl)([CH3:13])[CH3:12].[NH4+].[Cl-].Cl>CCOCC.C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]([OH:8])[CH:11]([CH3:13])[CH3:12])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CC(C)[Mg]Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(O)c1cc(Br)ccc1O
Reaction time: 0.25 h
Yield: 122.2 %

Procedure:
The 5-bromo-2-hydroxybenzaldehyde (4.00 g, 19.9 mmol) in Et2O (40.0 mL) and THF (10.0 mL) was added dropwise to the isopropylmagnesium chloride (2 M in Et2O, 29.8 mL, 59.7 mmol) at ambient temperature. The reaction was stirred for about 15 min then MeOH (5 mL) was added followed by saturated aqueous NH4Cl and 1 N HCl. The reaction was extracted with EtOAc and then the combined organic layers were extracted with brine, dried over MgSO4, filtered, and evaporated to give the title compound as an oil (5.96 g, >100% yield). NMR showed some EtOAc but it was used as is the next step: 1H NMR (DMSO-d6, δ) 0.87 (3H, d), 1.03 (3H, d), 2.06 (1H, m), 2.77 (1H, s), 4.49 (1H, d), 6.78 (1H, d), 7.02 (1H, s), 7.25 (1H, dd), 8.11 (1H, s)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)=[O:17])=[C:12]([C:25]([NH:27][C@H:28]3[CH2:34][CH2:33][CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]3)=[O:26])[CH:11]=2)=[CH:6][CH:5]=1>CO.O1CCOCC1>[NH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][C@H:28]([NH:27][C:25]([C:12]2[CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[S:14][C:13]=2[NH:15][C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)=[O:17])=[O:26])[CH2:29]1
Reactant: COc1ccc(-c2cc(C(=O)N[C@H]3CCCCN(C(=O)OC(C)(C)C)C3)c(NC(=O)Nc3cnccn3)s2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(C(=O)N[C@H]3CCCCNC3)c(NC(=O)Nc3cnccn3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
hydrochloride. To a stirred solution of tert-butyl(3S)-3-{[(5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}azepane-1-carboxylate (0.51 g, 0.9 mmol) in 10 mL of MeOH is added 10 mL (40 mmol) of 4.0 N HCl in dioxane. The solution was stirred at room temperature for 4 h and then concentrated under vacuum. The residue was partially recrystallized by triturating in refluxing 2-propanol to yield the title compound are a light orange solid (0.30 g, 67%). 1H NMR (d6-DMSO δ 12.6, br s, 1H; δ 10.9, s, 1H; δ 9.55, br s, 1H; δ 9.24, br s, 1H; δ 8.88, s, 1H; δ 8.49, d, 1H; δ 8.35, dd, 1H; δ 8.29, d, 1H; δ 7.92, s, 1H; δ 7.54, d, 2H; δ 6.99, d, 2H; δ 4.42, m, 1H; δ 3.33, m, 1H; δ 3.23, m, 2H; δ 3.10, m, 1H; δ 2.02, m, 1H; δ 1.85, m, 4H; δ 1.62, m, 1H;), LC/MS (APCI, ES, M+H=467).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.[CH3:23][O:24][CH2:25][CH2:26]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH2:26][CH2:25][O:24][CH3:23])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: COCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: COCCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Yield: 100.5 %

Procedure:
3.3 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetic acid and 1.5 g of 2-methoxyethanol were dissolved in 50 ml of benzene, followed by addition of 0.5 g of p-toluene sulfonic acid. Then, the mixture was heated under reflux for 3 hours. After completion of the reaction, to the reaction mixture was added 50 ml of ether. The resulting mixture was washed with water by the customary method and dried over anhydrous sodium sulfate, followed by evaporation-removal of the solvent under reduced pressure, thereby to obtain 3.9 g of 2-methoxyethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetate.
Reaction SMILES: Cl.[I:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.O1CCOC[CH2:14]1>CO>[I:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1ccc(I)cc1
Reaction time: 8 h

Procedure:
A 4M solution of HCl in dioxane (50 mL) was added to 2-(4-iodophenyl)acetic acid (10 g, 38.2 mmol) in MeOH (100 mL) and the reaction stirred overnight. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-30% EtOAc in hexanes to afford methyl 2-(4-iodophenyl)acetate in 10.42 g (99%). LRMS: 276.0 (calc) 277.1 (found)(MH+)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][N:20]([CH3:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[C:21]([N:20]([CH3:19])[CH3:30])[CH:22]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: CN(C)c1cccc(C(=O)O)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(N(C)C)c3)CC2)ccc1Cl
Yield: 33 %

Procedure:
The title compound (14 mg, 33%) was prepared analogously to example 8 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 3-dimethylaminobenzoic acid. MS: 416.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:33]N(C=O)C>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][CH:33]=[C:23]([C:20]1[CH:19]=[CH:18][C:17]([C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=3)=[CH:22][CH:21]=1)[C:24]2=[O:26]
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: O=C(O)Cc1ccc(-c2ccc(F)cc2)cc1
Reactant: CN(C)C=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=c1c(-c2ccc(-c3ccc(F)cc3)cc2)coc2cc(O)c(Cl)cc12

Procedure:
This compounds was synthesised in the same manner as described above. 4-Chlororesorcinol (0.31 g, 2.17 mmol), (4′-fluorobiphenyl-4-yl)-acetic acid (0.5 g, 2.17 mmol), BF3Et2O (5 ml), PCl5 (0.68 g, 3.3 mmol), DMF (8 ml and 5 ml). 6-chloro-3-(4′-fluoro-biphenyl-4-yl)-7-hydroxy-chromen-4-one precipitated out as a white solid (0.45 g, 68.6%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:25][S:22]([C:19]1[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=1)(=[O:24])=[O:23]
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Yield: 39.9 %

Procedure:
A mixture of methyl 10-bromodecanoate (1.5 g, 0.006 mol), 4-chlorobenzenesulphonamide (3.44 g, 0.018 mol), potassium carbonate (6.2 g, 0.045 mol) and dimethylformamide (50 ml) was heated at 100°-120° C. for 3 hours. After cooling, the inorganic material was removed by filtration. The filtrate was evaporated to dryness and the residue was extracted with dichloromethane. The residual oil obtained by evaporation was chromatographed on silica gel in petroleum ether (40°-60° C.) and the solid obtained on evaporation of the eluate was recrystallised (ether-pet. ether 40°-60°) to give the title compound (0.9 g, m.p. 68°-70° C.).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:20]=[N:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[N:22]1[N:21]=[C:20]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:15])[CH3:14])[C:2]([Br:1])=[CH:3][CH:4]=3)[N:9]=2)[N:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=12
Reactant: CC(C)(C)[Si](C)(C)Oc1c(Br)ccc2ccc(C=NNc3ccccn3)nc12
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1c(Br)ccc2ccc(-c3nnc4ccccn34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To the product from Step D (2.95 g, 6.45 mmol) was added CH2Cl2 (60 mL). Iodobenzene diacetate (2.28 g, 7.09 mmol) was added and the mixture stirred at ambient temperature overnight. The mixture was concentrated and the product purified directly by column chromatography (1 to 8% MeOH/CH2Cl2) to afford 2.87 g (88%) of the product.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35]2[S:39][N:38]=[CH:37][N:36]=2)[CH2:24][CH2:23]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.SCC(O)=O>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][NH:9][C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35]2[S:39][N:38]=[CH:37][N:36]=2)[CH2:24][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1c1ncns1
Agent: O=C(O)CS
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1c1ncns1
Temperature: 30 °C
Reaction time: 24 h
Yield: 71.7 %

Procedure:
To a mixture of (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-(1,2,4-thiadiazol-5-yl)piperidine-1-carboxylate (1.17 g, 2.0 mmol) in dry DMF (30 mL) at rt was added LiOH.H2O (640 mg, 16.0 mmol), followed by addition of 2-mercaptoacetic acid (920 mg, 10.0 mmol). The mixture was stirred at 30° C. for 24 hrs., then the mixture was diluted with EtOAc (200 mL), washed with water (4×), dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to give (2S,5R)-tert-butyl 5-(benzyloxyamino)-2-(1,2,4-thiadiazol-5-yl)piperidine-1-carboxylate (560 mg, 75%) as an oil. ESI-MS (EI+, m/z): 413 [M+Na]+.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)=[O:4].[OH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH:12]1[C:10]2[CH2:11][N:5]([C:3](=[O:4])[CH2:2][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=3)[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][C:9]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)N1Cc2ccccc2Oc2ccccc21
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCC(=O)N2Cc3ccccc3Oc3ccccc32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
Title compound 455 (0.890 g, 2.81 mmol) and the methyl 4-hydroxybenzoate (0.512 g, 3.37 mmol) were dissolved in acetonitrile (10.0 mL) and the cesium carbonate (1.83 g, 5.62 mmol) was added. The reaction mixture was stirred at 100° C. in a sealed tube for 4 hours. The mixture was cooled down to room temperature and diluted with ethyl acetate. The organic layer was washed with water (2 times) and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (30-40% ethyl acetate in hexanes) to afford title compound 456 (355 mg, 32%) as white foam. MS (m/z): 390.3 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([OH:23])=[CH:18][CH:19]=4)[C:14]3=[O:24])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:29][CH2:28][CH2:27][O:23][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][N:13]([C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=3[CH3:12])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:25])[C:14]2=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(O)cc2c1=O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OCCCl)cc2c1=O

Procedure:
N-Cyclopropyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide (0.56 g), 1-bromo-2-chloroethane (0.7 ml) and potassium carbonate (2.32 g) were stirred in DMF (20 ml) at 50° C. for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated to give 3-[7-(2-chloroethoxy)-1-oxoisoquinolin-2(1H)-yl]-N-cyclopropyl-4-methylbenzamide as a cream coloured solid (0.57 g); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.10 (s, 3H), 2.86 (m, 1H), 4.00 (t, 2H), 4.40 (m, 2H), 6.73 (d, 1H), 7.23 (d, 1H), 7.47 (d, 1H), 7.49 (d, 1H), 7.68 (s, 1H), 7.73 (m, 2H), 7.88 (d, 1H), 8.44 (d, 1H); Mass Spectrum: M+Na+ 419.
Reaction SMILES: [CH2:1]([CH:5]([CH2:9][NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:21].OO>O>[CH2:1]([CH:5]([CH2:9][NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([OH:8])=[O+:7][O-:21])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: CCCCC(CNCCC(=O)O)C(=O)O
Agent: OO
Solvent: O
Product: CCCCC(CNCCC(=O)O)C(O)=[O+][O-]
Temperature: 50 °C

Procedure:
100 g butyl imino dipropionic acid (0.46 mol) from example 7a was dissolved in 100 g H2O, whereupon 0.10 g EDTA was added and the temperature was increased to 50° C. After 30 minutes 3.2 g (0.475 mol) 50% hydrogen peroxide was added by drops during 20 minutes and the mixture reacted for 2 hours at 75° C. under a reflux cooler. Then the water was evaporated at 40° C. until a slightly yellow-brown oil formed.