Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25]([C:28]([CH3:32])([CH3:31])[C:29]#[N:30])=[N:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:39].[Na+]>CC(O)C>[C:33]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25]([C:28]([CH3:32])([CH3:31])[C:29]([NH2:30])=[O:39])=[N:26][N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: [OH-]
Reactant: CC(C)(C#N)c1nnc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C(N)=O)c1nnc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Temperature: 40 °C

Procedure:
409 mg of 2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionitrile was dissolved in 6 ml of 2-propanol; 3.5 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring under heating at an external temperature of 40° C. for 12 hours. After cooling, the 2-propanol was distilled off; the residue was extracted with ethyl acetate-tetrahydrofuran (1:1), washed with saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the residue was crystallized from ethyl acetate-diethyl ether (1:1), washed with diethyl ether, and dried, to yield 293 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:3]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:4]=3[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=2)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Agent: O=Cc1cccc(B(O)O)c1
Product: CN1C(=O)CN=C(c2ccc(F)cc2)c2cc(-c3ccccc3)ccc21
Yield: 14 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 4-fluorophenyl boronic acid. The title compound (19 mg) was obtained as a beige solid, (yield=14%).
Reaction SMILES: C([N:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([CH2:14]Br)[NH:6][C:5]1=[O:16])(=O)C.[C:17]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:35]>CC(O)C.O.C(O)C>[ClH:35].[C:17]1([CH:23]2[CH2:24][CH2:25][N:26]([CH2:14][C:7]3[NH:6][C:5](=[O:16])[NH:4][C:8]=3[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:27][CH2:28]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(CBr)[nH]c(=O)n1C(C)=O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Solvent: CCO
Product: CCOC(=O)c1[nH]c(=O)[nH]c1CN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4.4 g (15 mmole) of ethyl 3-acetyl-5-(bromomethyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate 2.5 g (16 mmole) of 4-phenylpiperidine, 2.1 g (15 mmole) of potassium carbonate and 75 ml of ethanol is stirred at 25° C. for 16 hours. Water (100 ml) is added and a precipitate forms. This is separated by filtration and washed with water. It is then suspended in 2-propanol and 1 equivalent of hydrogen chloride in 2-propanol is added. The resulting solid is separated by filtration and recrystallized from 2-propanol containing a little water to give ethyl 2,3-dihydro-5-[(4-phenyl-1-piperidinyl)methyl]-2-oxo-1H-imidazole-4-carboxylate hydrochloride melting at about 240°-241° C.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36](=[O:46])[CH2:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[C:40](Br)[CH:39]=1>>[CH3:34][O:35][C:36](=[O:46])[CH2:37][C:38]1[CH:39]=[C:40]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]=2[CH2:11][N:10]([CH2:31][CH3:32])[C:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:33])[CH:41]=[C:42]([Cl:44])[CH:43]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)NCc1ccccc1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 3-benzyl-1-ethyl-1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-urea and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: [C:1]([O:8][CH2:9]I)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:11][O:12][N:13]=[C:14]([C:37]1[N:38]=[C:39]([NH2:42])[S:40][CH:41]=1)[C:15]([NH:17][CH:18]1[C:35](=[O:36])[N:20]2[C:21]([C:32]([O-:34])=[O:33])=[C:22]([CH2:25][S:26][C:27]3[S:28][CH:29]=[N:30][N:31]=3)[CH2:23][S:24][C@H:19]12)=[O:16].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[CH3:11][O:12][N:13]=[C:14]([C:37]1[N:38]=[C:39]([NH2:42])[S:40][CH:41]=1)[C:15]([NH:17][CH:18]1[C:35](=[O:36])[N:20]2[C:21]([C:32]([O:34][CH2:9][O:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:33])=[C:22]([CH2:25][S:26][C:27]3[S:28][CH:29]=[N:30][N:31]=3)[CH2:23][S:24][C@H:19]12)=[O:16]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Reactant: CCCCCC(=O)OCI
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(=O)OCOC(=O)C1=C(CSc2nncs2)CS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
A solution of iodomethyl hexanoate (1.58 g.) in dimethylformamide (3 ml.) was added at a time under ice-cooling to a stirred solution of sodium 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (3.0 g.) in dimethylformamide (15 ml.). The mixture was stirred for 10 minutes at the same temperature and poured into a mixture of water (50 ml.) and ethyl acetate (100 ml.). The aqueous layer was separated and extracted twice with ethyl acetate (50 ml.). The combined ethyl acetate layer was filtered and the filtrate was washed three times with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo to a volume of 20 ml. to give precipitates, which were collected by filtration, washed with ethyl acetate (10 ml.) and dried to give hexanoyloxymethyl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (2.1 g.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28](I)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]([C:47]([F:50])([F:49])[F:48])[C:43]([NH2:46])=[N:44][CH:45]=2)O1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>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.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28]([C:40]5[CH:45]=[N:44][C:43]([NH2:46])=[C:42]([C:47]([F:50])([F:49])[F:48])[CH:41]=5)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2nn3c(I)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Yield: 7 %

Procedure:
A mixture of 4-[4-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxy-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (94 mg, 0.169 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (73 mg, 0.253 mmol, 1.5 eq), 1,4-dioxane (5 ml), K2CO3 (70 mg, 0.507 mmol, 3 eq), H2O (2 ml) and Pd(PPh3)2Cl2 (12 mg, 0.0169 mmol, 0.1 eq) was heated under microwave irradiation (120° C., 30 min). Solvents were removed and the residue was partitioned between H2O and EtOAc. The organic layer was dried, filtered and evaporated. The residue was purified in an Isolute Flash Si II column (10-25% EtOAc in c-hexane and 20% MeOH in DCM) and by HPLC-prep to give the desired product (7 mg) as a yellow solid. The aqueous phase was further extracted with MeOH/DCM 1:9, the organic layers were dried, filtered and evaporated. The residue was triturated with MeOH/DMSO, filtered and washed with CH3CN to give the desired product (18 mg, overall yield: 25%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=2.95 min, [M+H]+ m/z 591.2; 1H NMR (300 MHz, DMSO) δ 8.86 (d, J=1.8 Hz, 1H), 8.43 (d, J=2.1 Hz, 1H), 7.77 (s, 1H), 7.49 (m, 2H), 7.27 (d, J=9.2 Hz, 1H), 6.73 (s, 2H), 4.67 (m, 1H), 3.89 (s, 3H), 3.68 (m, 2H), 3.21 (m, 2H), 1.92 (m, 2H), 1.57 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][C:22]3[N:21]4[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:15][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]4[CH2:49][O:48][CH2:47]4)[CH2:42][CH:41]3[CH2:50][CH3:51])=[CH:36][N:35]=2)[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[CH2:50]([C@H:41]1[CH2:42][N:43]([CH:46]2[CH2:47][O:48][CH2:49]2)[CH2:44][CH2:45][N:40]1[C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]2[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=[C:27]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[CH2:24][CH2:23][C:22]5[N:21]6[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]6)=[CH:15][C:14]=5[C:13]4=[O:25])[CH:10]=[C:9]([F:26])[CH:8]=3)[CH:32]=2)=[N:35][CH:36]=1)[CH3:51]
Reactant: CCC1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCc5c(cc6n5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCc5c(cc6n5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
A mixture of 123a (105 mg, 0.15 mmol) and lithium hydroxide (36 mg, 1.5 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 123 (40 mg, 40%) as a pale pink solid. MS: [M+H]+ 682.3. 1H NMR (500 M, CHCl3) δ 8.55 (s, 1H), 7.93 (s, 1H), 7.82 (s, 1H), 7.51 (s, 1H), 7.29 (d, J=3.5 Hz, 1H), 7.15-7.12 (m, 1H), 6.94 (dd, J=3.5 Hz, 10.5, 1H), 6.81 (d, J=10.0 Hz, 1H), 6.30 (s, 1H), 4.77-4.74 (m, 4H), 4.72-4.70 (m, 1H), 4.57-4.55 (m, 1H), 4.29-4.24 (m, 1H), 4.12-4.05 (m, 1H), 3.90-3.78 (m, 4H), 3.70 (s, 3H), 3.52-3.50 (m, 1H), 3.32-3.30 (m, 1H), 3.12-3.10 (m, 2H), 3.04-2.83 (m, 2H), 2.81 (m, 2H), 2.57-2.50 (m, 1H), 2.43-2.33 (m, 2H), 2.05-2.00 (m, 2H), 1.87-1.85 (m, 2H), 1.49-1.35 (m, 2H), 0.81 (t, J=8.5 Hz, 3H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>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.O>[C:4]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][C:17]([C:27]3[CH:28]=[CH:29][C:24]([C:21](=[O:23])[CH3:22])=[CH:25][CH:26]=3)=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 80 °C
Yield: 75.8 %

Procedure:
4-Bromotriphenylamine (2.0 g, 6.17 mmol), 4-acetylphenylboronic acid (1.12 g, 6.8 mmol), dichlorobis(triphenylphosphine)palladium(II) (130 mg, 0.185 mmol) and sodium carbonate (460 mg, 4.32 mmol) were added into a solvent mixture of acetonitrile and water (1:1, v/v, 80 mL), and heated under nitrogen at 80° C. for 3 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature and added with water (80 mL), followed by the separation of the organic layer with dichloromethane (150 mL×3). The organic layer was filtered, dried and evaporated, and the resulting organic residue was purified by column chromatogram (silica gel, hexane: EtOAc=4:1) to obtain the title compound (1.7 g).
Reaction SMILES: O[N:2]=[CH:3][C:4]1[S:8][C:7]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=2[CH3:18])=[CH:6][CH:5]=1>N1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:3]([C:4]1[S:8][C:7]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=2[CH3:18])=[CH:6][CH:5]=1)#[N:2]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C=NO)s2)s1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(C)c(-c2ccc(C#N)s2)s1
Temperature: 25 °C

Procedure:
N-(5-{5-[(hydroxyimino)methyl]-2-thienyl}-4-methyl-1,3-thiazol-2-yl)acetamide, Compound (14) (100 mg; 0.36 mmol; 1 eq.), is heated with copper acetate (3.3 mg; 0.018 mmol; 0.05 eq.) in neat pyridine (5 ml) at 75° C. for 1 hour. Reaction mixture is cooled down to room temperature and solvents are evaporated to dryness. The crude material is dissolved in dichloromethane, washed with water (10 ml) and dried over MgSO4. After evaporation of the solvents, the crude product is purified by flash chromatography using cyclohexane/ethyl acetate (90/10) as eluent. Compound (15) is obtained as a yellow powder (42 mg; 44%). 1H NMR (CDCl3, 300 MHz) δ 2.22 (s, 3H), 2.43 (s, 3H), 7.01 (d, J=6 Hz, 1H), 7.50 (d, J=6 Hz, 1H). M-(ESI): 262.3; M+(ESI): 264.3. HPLC, Rt: 3.03 min (purity: 91%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:25]=[CH:24][C:16]2[C:17]([CH3:23])([CH3:22])[O:18][C:19](=[O:21])[NH:20][C:15]=2[CH:14]=1.[OH:26]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:25]=[CH:24][C:16]2[C:17]([CH3:22])([CH3:23])[O:18][C:19](=[O:21])[NH:20][C:15]=2[CH:14]=1)=[O:26]
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCSc3ccccn3)ccc21
Product: CC1(C)OC(=O)Nc2cc(OCCCCS(=O)c3ccccn3)ccc21

Procedure:
Prepared analogously to Example 2 from 7-[4-(2-pyridylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12](Br)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[CH2:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([CH:17]=[CH:16][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C=Cc2ccncc2)cc(C(=O)OC)c1
Yield: 65 %

Procedure:
A solution of 5-bromoisophthalic acid dimethylester (542 mg, 2 mmol) and 4-vinylpyridine (206 mg, 2 mmol), Pd(OAc)2 (8 mg), tri-o-tolylphosphine (30 mg) in 5 ml Et3N (5 ml) was stirred at 80° C. for overnight. The reaction mixture was purified by silica gel column eluted by 50% EtOAc in hexane to afford the product (65% yield). MS+=297. 1H NMR (CDCl3, 400 MHz) 8.64 (s, 1H), 8.61 (d, 2H), 8.38 (d, 2H), 7.40 (m, 2H), 7.35 (m, 1H), 7.21 (m, 1H), 4.02 (s, 6H);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO.COC(OC)(C)C>[CH3:22][O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Solvent: O
Solvent: CO
Solvent: COC(C)(C)OC
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1
Reaction time: 288 h

Procedure:
1.5 gm (50 millimols) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid, m.p. 164°- 165° C, were dissolved in 3 ml of methanol and 1.2 ml of 2,2-dimethoxypropane, 100 mgm of p-toluenesulfonic acid were added to the solution, and the mixture was allowed to stand for 12 days at room temperature. Then, water was added and the ester was extracted with toluene. The organic extract was washed with water, dried and evaporated, and the residue was purified by chromatography on 75 gm of silicagel (grain size 0.05 - 0.2 mm) with cyclohexane/ethyl acetate = 1/4. The combined ester -containing fractions were evaporated, and the residue was recrystallized from 3 ml of isopropanol. Yield: 800 mgm (50% of theory); m.p. 77-79° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([C:13]2[CH:17]=[CH:16][O:15][CH:14]=2)[C:10]2[C:5](=[CH:6][C:7](I)=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].C[Si](C)(C)CC[SH:23].CC(C)([O-])C.[K+]>CCO>[C:1]([C:3]1[CH:12]=[C:11]([C:13]2[CH:17]=[CH:16][O:15][CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([SH:23])=[CH:8][CH:9]=2)[CH:4]=1)#[N:2]
Reactant: C[Si](C)(C)CCS
Reactant: N#Cc1cc(-c2ccoc2)c2ccc(I)cc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1cc(-c2ccoc2)c2ccc(S)cc2c1
Reaction time: 1.5 h

Procedure:
A mixture of 2-cyano-4-(3-furyl)-7-iodonaphthalene (1 g), 2-(trimethylsilyl)ethane thiol (390 mg), potassium tert-butoxide (650 mg) and tetrakis (triphenylphosphine)palladium (100 mg) in EtOH (5 mL) was reluxed for 90 min. The solvent was evaporated and the residue partitioned between Et2O and H2O. The organic phase was dried (MgSO4) and concentrated and the residue was dissolved in DMF (24 mL). To this solution was added Bu4NF (7.7 mL of a 1M THF solution). After 30 min., 1N HCl was added followed by H2O. The precipitate that formed was filtered and washed with H2O to provide the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2ccc(OS(C)(=O)=O)cc2CC1
Yield: 102.5 %

Procedure:
A solution of 3-(tert-butyloxycarbonyl)-7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine (3.0 g, 0.011 mol), methanesulfonylchloride (1.44 g, 0.013 mol), triethylamine (1.27 g, 0.013 mol) and dichloromethane (50 ml) was stirred at room temperature for 18 h. The reaction mixture was then partitioned between dichloromethane (50 ml) and a saturated solution of sodium hydrogen carbonate (50 ml). The organic layer was separated, washed with water (50 ml) and then dried (Na2SO4). The solvent was then evaporated in vacuo to give the title compound (3.85 g, 99%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[C:7](SC)=[N:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]2=[N:4][N:3]=1.[C:15](OCC)(=[O:18])C=C.C[O-].[Na+].COC1C(Cl)=NC(SC)=NC=1.NN.N#CBr>CO>[NH2:1][C:2]1[N:6]=[C:5]2[N:4]([C:7]([O:18][CH3:15])=[N:8][CH:9]=[C:10]2[O:11][CH3:12])[N:3]=1
Reactant: COc1cnc(SC)n2c(N)nnc12
Reactant: C=CC(=O)OCC
Agent: COc1cnc(SC)nc1Cl
Agent: C[O-]
Agent: N#CBr
Solvent: CO
Product: COc1cnc(OC)n2nc(N)nc12

Procedure:
In U.S. Pat. No. 5,858,924, 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine is prepared from 3-amino-8-methoxy-5-methylthio[1,2,4]triazolo-[4,3-c]pyrimidine by treatment with ethyl acrylate and sodium methoxide in methanol. The 3-amino-8-methoxy-5-methylthio[1,2,4]triazolo[4,3-c]pyrimidine in turn is prepared from 5-methoxy-4-chloro-2-methylthio-pyrimidine by treatment with hydrazine followed by cyclization with cyanogen bromide. It would be advantageous to produce 2-amino-5,8-dimethoxy[1,2,4]-triazolo[1,5-c]pyrimidine more efficiently and in higher yield. It would also be advantageous to avoid the use of methylthio containing intermediates and the use of ethyl acrylate in the rearrangement of a [1,2,4]triazolo[4,3-c]pyrimidine into a [1,2,4]-triazolo[1,5-c]pyrimidine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([NH2:16])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[C:20]([N:22]=[C:23]=[O:24])=[O:21]>C(OCC)(=O)C>[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[C:20]([NH:22][C:23]([NH:16][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=2)[O:15][N:14]=1)=[O:24])=[O:21]
Reactant: CC(C)(C)c1ccc(-c2cc(N)no2)cc1
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(-c2cc(NC(=O)NC(=O)c3ccccc3Cl)no2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(4-tert-Butylphenyl)-3-aminoisoxazole (1 gram) and 2 chlorobenzoyl isocyanate (1.5 ml.) were mixed in 50 ml. of ethyl acetate. The reaction mixture was stirred for 3 hours at room temperature, solvent removed, and the product separated by filtration, m.p., 213°-214° C.
Reaction SMILES: C([Mg]Br)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[C:12]#[N:13].CN(C)[CH:18]=[O:19].O>O1CCCC1>[F:15][C:10]1[CH:9]=[CH:8][C:7]([CH:18]=[O:19])=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: CN(C)C=O
Reactant: N#Cc1cc(Br)ccc1F
Agent: CC(C)[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C=O)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iso-propyl magnesium bromide (18 ml, 1M in tetrahydrofuran, 18 mmol) was added dropwise to an ice-cooled solution of 5-bromo-2-fluorobenzonitrile (3 g, 15.1 mmol) in tetrahydrofuran (25 ml), and once addition was complete, the mixture was allowed to warm to room temperature and stirred for a further 2 hours. N,N-Dimethylformamide (3.5 ml, 45.2 mmol) was added and the reaction stirred for 3 hours. Water was added and the mixture extracted with ethyl acetate (3×). The combined organic extracts were washed with 6% aqueous magnesium sulphate solution, and brine, then dried (Na2SO4) and concentrated under reduced pressure. The product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:hexane (10:90 to 20:80) to afford the title compound as a light yellow solid, 1.01 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.Cl.[NH2:10][C@@H:11]([CH3:20])[C:12]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[O:13].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(OC(=O)C)C>[Br:1][C:2]1[N:3]=[C:4]([NH:10][C@@H:11]([CH3:20])[C:12]([NH:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)C(=O)NCC(F)(F)F
Reactant: Fc1cccc(Br)n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1cccc(Br)n1)C(=O)NCC(F)(F)F
Temperature: 220 °C
Yield: 65.7 %

Procedure:
A solution of 2-bromo-6-fluoropyridine (1.23 g, 7 mmol) and (S)-2-amino-N-(2,2,2-trifluoroethyl)propanamide hydrochloride (FF) (1.44 g, 7 mmol) in NMP (10 mL) was treated with DIPEA (2.4 mL, 14 mmol) and heated at 220° C. for 40 min in the microwave. After complete reaction, the mixture was diluted with ethylacetate (100 mL) then washed with water (5×25 mL), brine (1×25 mL) then dried over Na2SO4. The solvent was removed and the residue purified with silica-gel chromatography using hexane:ethyl acetate (4:1) to afford 1.5 g (66% yield) of a white solid, GG. LC-MS: 2.8 min, 327.8 ES+; 1H NMR (500 MHz, dmso-d6) d 8.56 (m, 1H), 7.29 (t, 1H), 7.13 (d, 1H), 6.68 (d, 1H), 6.55 (d, 1H), 4.36 (m, 1H), 3.90 (m, 2H), 1.30 (d, 3H).