Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:23]2[CH:24]=[C:19]([CH3:18])[CH:20]=[CH:21][CH:22]=2)[CH:5]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1cccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)c1
Yield: 10 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3-methylphenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (16 mg, 10%) which was obtained as a white solid. MS (ESI): m/e=315.0 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13](OCC)(=[O:15])C>>[CH:1]1([C:7]2[S:11][C:10]([N:12]=[C:13]=[O:15])=[N:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1nnc(C2CCCCC2)s1
Reactant: CCOC(C)=O
Product: O=C=Nc1nnc(C2CCCCC2)s1
Reaction time: 16 h

Procedure:
A saturated solution of phsogene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-cyclohexyl-2-amino-1,3,4-thiadiazole (50 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-cyclohexyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [C:1]([Cl:5])(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)CO)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[CH3:6][O:7][C:8]1([C:14]2[CH:21]=[C:20]([CH:19]=[CH:16][CH:15]=2)[CH2:1][Cl:5])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: COC1(c2cccc(CO)c2)CCOCC1
Reactant: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC1(c2cccc(CCl)c2)CCOCC1
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
Carbon tetrachloride (30.3 g, 198 mmol) was added dropwise over 20 minutes to a solution of 3-(4-methxytetrahydropyran-4-yl)benzyl alcohol from Step 4 (29.3 g, 132 mmol) and HMPA (32.2 g, 198 mmol) in THF (400 mL) at 0°-5° C. The mixture was stirred for 10 minutes and then concentrated. Excess Et2O was added and the mixture filtered through a celite pad. The filtrate was concentrated and chromatographed on silica gel using 20% EtOAc in hexane as eluent to obtain 24 g (81%) of the title compound as an oil.
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[N:19]3[C:9]4=[C:10]([C:13]5[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:11][CH2:12][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2.[OH-].[K+].[CH2:27](Br)[CH3:28]>C(O)C>[CH3:1][CH2:2][C@:3]12[CH:21]=[C:20]([C:22]([O:24][CH2:27][CH3:28])=[O:23])[N:19]3[C:9]4=[C:10]([C:13]5[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:11][CH2:12][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2
Reactant: CC[C@@]12C=C(C(=O)O)n3c4c(c5ccccc53)CCN(CCC1)[C@H]42
Reactant: CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C[C@]2(CC)CCCN3CCc4c(n1c1ccccc41)[C@@H]32
Yield: 66 %

Procedure:
1 g. (0.0031 moles) of apovincaminic acid and 0.17 g. (0.003 moles) of potassium hydroxide are dissolved in 80 ml. of anhydrous ethanol, thereafter 0.4 g. (0.0036 moles) of ethyl bromide are added to the solution. The solution is boiled under reflux for 3 hours. The reaction is monitored by layer chromatography. The solution is cooled and evaporated to dryness under reduced pressure. The dry residue is dissolved in 500 ml. of 2% aqueous sulfuric acid, and the solution is filtered. The pH of the filtrate is adjusted to 8 with 5% aqueous sodium hyrodxide solution. A small amount of precipitate separates. The mixture is extracted with 200 ml. portions of methylene chloride until no positive Mayer reaction can be observed in the aqueous phase. The organic phases are separated, combined, dried over anhydrous potassium carbonate, filtered and evaporated to dryness under reduced pressure. The dry residue is dissolved in 10 ml. of anhydrous ethanol, and the solution is left to crystallize at 0° to 2° C for 10 hours. 0.66 g. of apovincaminic acid ethyl ester are obtained (yield: 66%). On the basis of layer chromatography, a uniform product is formed. M.p.: 144° C (Boetius).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@@H:17]([CH2:21][CH:22]1[CH2:24][CH2:23]1)[C:18]([NH2:20])=[O:19]>>[C:18]([C@@H:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH2:21][CH:22]1[CH2:24][CH2:23]1)(=[O:19])[NH2:20]
Reactant: NC(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (S)-α-amino-cyclopropanepropanamide (CAN 156077-93-9) as starting materials and isolated (18 mg, 53%) as white solid; MS (ESI, m/z): 338.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[I:10](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.C([O-])([O-])=O.[Ca+2]>C(Cl)Cl.CO.CCOCC>[Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][C:6]([I:10])=[C:4]([CH:3]=1)[NH2:5]
Reactant: Cc1ccc(N)cc1Cl
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: Cc1cc(I)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
3-Chloro-4-methylaniline (1.50 g, 10.6 mmol) and benzyltrimethylammonium dichloroiodate (4.60 g, 13.2 mmol) were dissolved in CH2Cl2 (50 mL) and MeOH (20 mL), then CaCO3 (3.10 g, 31.0 mmol) was added and the reaction stirred at room temperature overnight. The reaction was diluted with Et2O (200 mL), filtered through Celite®, and concentrated. The crude material was purified by column chromatography using 97.5/2.5 hexane/EtOAc, giving the product (1.80 g, 63%) as light tan solids. MS (DCI) m/e 268 and 270 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 6.76 (s, 1H), 4.00 (v br s, 2H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][NH:4][C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37](O)=[O:38].F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:26][CH:2]([CH3:1])[CH2:3][N:4]([C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[O:12])[CH2:8][NH:7][CH2:6]1)[C:37]([C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]=1)=[O:38]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CN(C(=O)c1ccc2ccccc2n1)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Reaction time: 16 h

Procedure:
A 0.08M solution (1000 μL, 80 μmol) of tert-butyl (3S, 5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate in DMF and quinoline-2-carboxylic acid (15.2 mg, 88 μmol) were mixed, a 0.32M solution (500 μL, 160 μmol) of chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate and N,N-diisopropylethylamine in DMF was added at room temperature and the mixture was stirred for 16 hr. After completion of the reaction, 2% aqueous sodium hydrogen carbonate solution (1.0 ml) was added, and extracted with ethyl acetate (3.5 ml). The organic layer was separated by upper layer Phase Septube (manufactured by Wako Pure Chemical Industries, Ltd.). The solvent was evaporated under reduced pressure, and the residue was dissolved in DMSO-methanol (1:1) (1 ml), purified by preparative HPLC, and the object fraction was concentrated to give a protected title compound. 1M MSA acetonitrile solution (3 ml) was added to the obtained protected compound, and the mixture was stirred at room temperature for 16 hr. After completion of the reaction, 1M DIEA acetonitrile solution (3.5 ml) was added, and the reaction mixture was directly developed by preparative HPLC to give the object product (12.3 mg).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:13](C(OCC)=O)[C:12]2=[O:30])=[CH:2]1>CN(C)C(=O)C.O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:30])[CH:13]=[C:14]([NH:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(NCc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1C=C(NCc2ccc(F)cc2)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 6.7 %

Procedure:
A solution of the compound (0.10 g, 0.31 mmol) of Example 45 in N,N-dimethylacetamide (3.0 mL) was refluxed for 7 h. Cooled to ambient temperature, the reaction mixture was diluted with water and the precipitate was collected by filtration. The solid was washed with water and diethyl ether then dried to afford the titled compound as solid (0.0070 g, y. 9%).
Reaction SMILES: [C:1]12([C:15](OC)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([C:11]([O:13][CH3:14])=[O:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[OH:16][CH2:15][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([C:11]([O:13][CH3:14])=[O:12])([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C12CC3CC(CC(CO)(C3)C1)C2
Reaction time: 3 h
Yield: 18.6 %

Procedure:
After dissolving dimethyl 1,3-adamantanedicarboxylate (1.00 g, 3.96 mmol) in tetrahydrofuran (5 mL), diisobutylaluminum hydride (0.95 M; 5.0 mL, 4.75 mmol) was added dropwise while cooling on ice, and then the mixture was further stirred for 3 hours while cooling on ice. After the reaction, water (0.2 mL) and then aqueous 15% NaOH (0.2 mL) were added dropwise at room temperature, and the mixture was stirred for 30 minutes. Next, water (0.6 mL) and anhydrous magnesium sulfate were added and stirred therewith, and the insoluble portion was filtered out. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to chromatography (50 g Merck Art. 9385, hexane:ethyl acetate=3:2) to obtain the title compound as a colorless oil (0.1648 g, 0.735 mmole) (19% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:18]([O:21]C(=O)C)(=[O:20])[CH3:19].C1(OC2C=CC=CC=2)C=CC=CC=1>>[C:18]([OH:21])(=[O:20])[CH3:19].[C:18]([OH:21])(=[O:20])[CH3:19].[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)O

Procedure:
This Example describes the preparation of a polyarylate polymer in a one-step process starting with bisphenol-A, acetic anhydride, isophthalic and terephthalic acids, and diphenyl ether without isolating the bisphenol-A diacetate.
Reaction SMILES: ClC1C(N)=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1.C(O)=O.[Cl:18][C:19]1[C:27]2[NH:26][CH:25]=[N:24][C:23]=2[CH:22]=[C:21]([NH:28]C=O)[CH:20]=1.CCO>C(OC(=O)C)(=O)C.Cl.[Pd]>[Cl:18][C:19]1[C:27]2[NH:26][CH:25]=[N:24][C:23]=2[CH:22]=[C:21]([NH2:28])[CH:20]=1
Reactant: O=CNc1cc(Cl)c2[nH]cnc2c1
Agent: [Pd]
Agent: Cl
Agent: Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: Nc1cc(Cl)c2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanolic solution of 6-chloro-2,4-dinitroaniline (2.4 g, 11 mmol) was stirred overnight with 100 mg of 10% Pd/C under H2. Reaction mixture was filtered and concentrated in vacuo to provide an oil which was dissolved in 10 ml of acetic anhydride and 10 ml of formic acid and stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding a brown oil which was characterized as 4-chloro-6-foramidylbenzimidazole in NMR analysis. The foramide was dissolved in 20 ml of HCl sat'd EtOH and stirred for 3 h at 25° C. The reaction mixture was purified in column chromotography (5% MeOH/EtOAc) to provide 0.89 g (5.3 mmol, 48% overall) of the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[N:2]=1.[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH:18]([CH3:23])[C:19](=O)[CH2:20]Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO>[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH:18]([C:19]1[N:7]=[C:3]2[CH:4]=[CH:5][CH:6]=[N:1][N:2]2[CH:20]=1)[CH3:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)CBr
Reactant: Nc1cccnn1
Solvent: CCO
Product: CC(NC(=O)OCc1ccccc1)c1cn2ncccc2n1
Temperature: 25 °C

Procedure:
A mixture of pyridazin-3-ylamine (2 g, 21.05 mmol) and (3-bromo-1-methyl-2-oxopropyl)-carbamic acid benzyl ester (7.5 g, 25.26 mmol) in EtOH (25 mL) was heated to reflux overnight. After completion, the reaction mixture was cooled to rt. EtOH was removed in vacuo. The residue was dissolved in EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-5% MeOH in DCM to provide (1-imidazo[1,2-b]pyridazin-2-yl-ethyl)-carbamic acid benzyl ester: LC-MS (ESI) m/z 297.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[O:55]1[N:59]=[CH:58][C:57]([C:60](Cl)=[O:61])=[N:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60]([C:57]2[CH:58]=[N:59][O:55][N:56]=2)=[O:61])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1cnon1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2cnon2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 33 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1,2,5-oxadiazole-3-carbonyl chloride as starting materials in 33% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.41 (s, 2H), 9.02 (s, 1H), 8.30 (m, 2H), 8.20 (s, 1H), 7.72 (s, 1H), 7.65 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 6.47 (s, 1H), 4.38 (m, 1H), 4.02 (m, 1H), 3.19 (m, 2H), 2.98 (m, 4H), 2.32 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C27H27ClN9O3 (M+H)+: m/z=560.2.
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.C(=O)[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)=O>C(N(CC)CC)C>[C:14]1([CH:13]=[CH:12][CH2:4][CH2:6][C:7]([OH:9])=[O:8])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=CC=Cc1ccccc1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=C(O)CCC=Cc1ccccc1
Temperature: 95 °C

Procedure:
7.2 g (0.05 mol) of Meldrum's acid and 6.6 g (6.3 ml, 0.05 mol) of cinnamaldehyde were weighed in to 50 ml of the mixture of formic acid and triethylamine prepared as described in Example 1. The reaction mixture was heated to 95° C. during 1 hour and maintained at the same temperature for 2 hours. The product was separated according to Example 1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[C:12](=[O:16])[CH2:13][CH2:14][O:15][C:10]=2[C:9]=1[CH2:19][CH2:20][CH3:21].C([O:24][C:25](=[O:48])[CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([O:44]CC)=[O:43])[CH:37]=2)=[O:35])[CH:31]=[CH:30][C:29]=1[OH:47])C>CCCCCC.C(OCC)(=O)C>[C:42]([C:38]1[CH:37]=[C:36]([C:34]([C:32]2[CH:31]=[CH:30][C:29]([O:47][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]3[CH:18]=[CH:17][C:11]4[C:12](=[O:16])[CH2:13][CH2:14][O:15][C:10]=4[C:9]=3[CH2:19][CH2:20][CH3:21])=[C:28]([CH2:27][CH2:26][C:25]([OH:48])=[O:24])[CH:33]=2)=[O:35])[CH:41]=[CH:40][CH:39]=1)([OH:44])=[O:43]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1O
Reactant: CCCc1c(OCCCCCBr)ccc2c1OCCC2=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 36 %

Procedure:
Starting with 0.275 g (0.78 mmol) of 7-[(5-bromopentyl)oxy]-2,3-dihydro-8-propyl-4H-1-benzopyran-4-one, and 0.286 g (0.77 mmol) of 5-[[3-(ethoxycarbonyl)phenyl]carbonyl]-2-hydroxybenzenepropanoic acid ethyl ester, 5-[(3-carboxyphenyl)carbonyl]-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid (0.163 g; 52% overall yield) was obtained, as a white solid, mp 122°-128° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 19.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][S:7]([C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:9])=[O:8])C.O.[OH-].[K+].Cl>C1COCC1>[CH2:14]([CH:5]([CH2:6][S:7]([C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:9])=[O:8])[C:4]([OH:21])=[O:3])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
550 mg of 2-benzyl-3-tert.-butylsulphonyl-propionic acid ethyl ester are dissolved in 8 ml of THF and then reacted with 5 ml of water and 0.88 ml of 2N potassium hydroxide solution. The mixture is stirred overnight at room temperature, neutralised with 0.88 ml of 2N hydrochloric acid and concentrated by evaporation. The residue is purified by flash chromatography on 30 g of silica gel 60 (eluant H). Yellow oil; m/e 284; 1H-NMR (DMSO-d6): 1.27 ppm (s, 9H); 2.73-3.1 (m, 4H); 3.2-3.5 (m, 1H); 7.2-7.4 (m, 5H); 12.5 (s, 1H).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=O)[CH3:5].[O:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C:15]([NH2:17])=[S:16].CS(C)=O.Cl>O1CCCC1.C(OCC)(=O)C>[NH:17]=[C:15]1[N:14]([CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][O:8]2)[C:4]([CH3:5])=[C:3]([C:2](=[O:7])[CH3:1])[S:16]1
Reactant: NC(=S)NC[C@H]1CCCO1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(=O)c1sc(=N)n(C[C@H]2CCCO2)c1C
Temperature: 40 °C

Procedure:
To a solution of pentane-2,4-dione (451 mg, 4.5 mmol) and the product from Example 278A (786 mg, 4.5 mmol) in tetrahydrofuran (5 mL) was added a mixture of dimethylsulfoxide (0.64 mL, 9.0 mmol) and concentrated HCl (0.75 mL, 9.0 mmol). The reaction mixture was heated at 40° C. for 12 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic extract was dried (Na2SO4), filtered and concentrated to afford the title compound. MS (ESI) m/z 241 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH:12]([NH:15]C(C)C)([CH3:14])[CH3:13]>CO>[CH3:13][CH:12]([NH:15][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: ClCCCOc1cccnc1
Solvent: CO
Product: CC(C)NCCCOc1cccnc1
Temperature: 100 °C
Yield: 58.6 %

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (0.80 g, 4.66 mmol) was dissolved in methanol (25 mL) and added to diisopropylamine (25 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 100% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 0.531 g (58.6%) of a dark-brown oil. The compound exhibits a Ki of 8500 nM. The compound exhibits neurotransmitter release of 16 percent.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=[C:13]([Cl:22])[CH:12]=1.Cl>CCO>[Cl:22][C:13]1[CH:12]=[C:11]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=2[F:1])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=1
Reactant: Cc1ccc(N)c(F)c1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(C)cc1F
Yield: 44 %

Procedure:
2-Fluoro-4-methylaniline and ethyl 4,6-dichloronicotinate were reacted in a mixture of EtOH and conc. HCl as for example 33, step A. The resultant solid was isolated by filtration and washed with 10% Et2O/Hexane, to give ethyl 6-chloro-4-(2-fluoro-4-methylanilino)nicotinate (44%); m.p. (EtOH/water) 107-109° C. 1H NMR [400 MHz, CDCl3] δ 9.63 (br s, 1H), 8.77 (s, 1H), 7.20 (t, J=8.2 Hz, 1H), 7.05-6.99 (m, 2H), 6.65 (d, J=1.6 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). MS (FAB+) 309 (40%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:5]=[CH:6][C:7](=[O:16])[C:8]=1[O:9]C(=O)C(C)(C)C)[CH3:2]>O>[CH2:1]([C:3]1[N:4]([CH2:17][CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:5]=[CH:6][C:7](=[O:16])[C:8]=1[OH:9])[CH3:2]
Reactant: CCc1c(OC(=O)C(C)(C)C)c(=O)ccn1CCOC(=O)C(C)(C)C
Solvent: O
Product: CCc1c(O)c(=O)ccn1CCOC(=O)C(C)(C)C
Yield: 78.9 %

Procedure:
2-Ethyl-3-pivaloyloxy-1-(2-pivaloyloxyethyl)pyridin-4-one (0.5 g) was heated in distilled water (40 ml) at 70° C. for 3 hours. The water was removed by rotary evaporation and the residue dried under high vacuum. Recrystallization of the dry solid from ethyl acetate and petroleum ether (b.p. 40°-600° C.) gave the title compound (0.3 g, 69%) as colourless crystals with a melting point and infra-red and n.m.r. spectra as quoted in Example 2.