Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][NH:7][CH:8]([CH3:10])[CH3:9])[NH:3][CH:2]=1.[F-].[CH2:12]([N+](CCCC)(CCCC)CCCC)[CH2:13][CH2:14]C.[O:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:1]1[CH:5]=[C:4]([CH2:6][N:7]([CH:13]([CH3:14])[CH3:12])[C:8]2[CH:10]=[C:31]([CH2:30][OH:29])[CH:32]=[CH:33][CH:9]=2)[NH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)NCc1cnc[nH]1
Agent: [F-]
Product: CC(C)N(Cc1cnc[nH]1)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[3-tert-Butyl-dimethyl-silanyloxymethyl]phenyl]-(3H-imidazol-4-ylmethyl)-isopropyl-amine (0.724 g, 2 mmol) was dissolved in tetrahydrofuran (20 ml) and tetrabutylammonium fluoride solution (4 ml, 1M) in tetrahydrofuran was added. After stirring the mixture at room temperature overnight the solvent was evaporated and the residue was purified by flash chromatography (SiO2, eluent: ethyl acetate) to yield a colourless gum, (0.252 g, 51%); MS (ISP): 246.4 ((M+H)+.).
Reaction SMILES: [CH2:1]([Si:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Cl)=[CH:20][CH:19]=1.[Cl-].[NH4+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1.O1CCCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:7]2[CH2:8][CH2:9][Si:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([CH2:1][CH2:2][CH3:3])[CH2:5][CH:6]=2)=[CH:20][CH:19]=1
Reactant: CCC[Si]1(c2ccccc2)CCC(=O)CC1
Reactant: Cl[Mg]c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCC[Si]1(c2ccccc2)CC=C(c2ccc(Cl)cc2)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
10.0 g of 4-n-propyl-4-phenyl-4-silacyclohexanone was dripped into a 50 ml tetrahydrofuran solution of 1.0M p-chlorophenyl magnesium chloride at 40°-50° C. After stirring for 2 hours at 50° C., the mixture was poured into a saturated aqueous solution of ammonium chloride and extraction was conducted using benzene. 500 mg of p-toluenesulfonic acid monohydrate was then added to the benzene solution and refluxing was conducted while the water generated was distilled away. After the water stopped distilling away, the benzene layer was washed with an aqueous solution of sodium bicarbonate, dried and concentrated to obtain 4-(4-chlorophenyl)-1-phenyl-1-n-propyl-1-silacyclohex-3-ene. This was then dissolved in 50 ml of ethanol and hydrogenation was conducted using 1.0 g of palladium carbon as a catalyst. After the catalyst was filtered out, the product was concentrated to obtain 14.0 g of 4-(4-chlorophenyl)-1-phenyl-1-n-propyl-1-silacyclohexane.
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:15]2[O:16][CH2:17][CH2:18][O:19][C:14]=2[C:13]=1[CH2:22][CH3:23])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].O>O>[CH2:22]([C:13]1[C:14]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[CH:20]=[CH:21][C:12]=1[C:10]([NH:9][NH2:8])=[O:11])[CH3:23]
Reactant: CCc1c(C(=O)NNC(=O)OC(C)(C)C)ccc2c1OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(C(=O)NN)ccc2c1OCCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 129.9 %

Procedure:
5.15 g (16 mmol) of N′-(5-ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-hydrazinecarboxylic acid tert-butyl ester were added to a 200 mL round bottom flask. About 20 mL of trifluoroacetic acid were added and the reaction mixture was stirred at room temperature for 24 hours. Then about 40 mL of water were added, followed by the slow addition of cold 10% NaOH/H2O, with stirring, until the acid was neutralized (pH ˜14). The reaction mixture was transferred to a separatory funnel and extracted with ethyl acetate by shaking gently (caution: gas evolution). The ethyl acetate extract was dried and evaporated to yield 5.51 g of a pale, viscous yellow semi-solid. The material was then placed in a 50° C. vacuum oven for about 1 hour to yield 4.62 g of 5-ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid hydrazide. The t-Boc cleavage is best accomplished with neat trifluoroacetic acid; use of adjunctive solvents always resulted in much lower yields. 1H NMR (CDCl3, 500 MHz) δ (ppm): 7.0 (br, 1H), 6.83 (m, 1H), 6.71 (m, 1H), 4.28 (br s, 4H), 2.76 (m, 2H), 1.6 (br, 2H), 1.17 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:21]=[CH:20][C:19]3[C:14](=[C:15]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:16]=[CH:17][C:18]=3[Cl:22])[N:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:21]=[CH:20][C:19]3[C:14](=[C:15]([O:23][CH:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)[CH:16]=[CH:17][C:18]=3[Cl:22])[N:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:6]
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Nc2ncc3c(Cl)ccc(OC4CCNCC4)c3n2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Nc2ncc3c(Cl)ccc(OC4CCNCC4)c3n2)cc1Cl)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A mixture of 2-chloro-4-(5-chloro-8-(piperidin-4-yloxy) quinazolin-2-ylamino) benzoic acid (1 eq), morpholine (3 eq), HATU (1.5 eq) and DIEA (4 eq) in NMP was stirred at room temperature for 4 h. The reaction mixture was concentrated and purified by semi-prep HPLC to provide pure product in 50% yield. ES/MS m/z 502.3 (MH+).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:34])([F:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>CN(C=O)C>[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:29]([CH2:28][C:27]([F:34])([F:33])[F:26])(=[O:31])=[O:30])[CH2:22][CH2:21]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CC(F)(F)F)CC3)n[nH]c12
Yield: 20.5 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) (0.030 g, 0.07 mmol) was reacted with 2,2,2-trifluoroethanesulfonyl chloride (0.015 mL, 0.105 mmol) in the presence of triethylamine (0.04 mL, 0.28 mmol) in DMF (2 mL) to give 6.7 mg of white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][C:15]2([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16][C:15]3([CH3:24])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)Nc2ccc(-c3cccc(F)c3)cc21

Procedure:
Prepared by coupling 3-fluorophenylboronic acid with an equivalent amount of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one using a catalytic amount of tetrakis(triphenylphosphine)palladium(0) with overnight refluxing in toluene containing an equivalent amount of potassium carbonate dissolved in water. Work up in the usual manner followed by recrystallization from ethanol gave a gray solid: mp 190-192° C. 1H-NMR (DMSO-d6) δ 10.27 (s, 1H), 7.57 (s, 1H), 7.50 (m, 4H), 7.15 (m, 1H), 6.95 (d, 1H J=8.2 Hz), 2.39 (s, 2H), 1.29 (s, 6H); MS (APCI(−)) m/z 268 [M−H]− Anal. Calc. For C17H16FNO 0.25 H2O: C, 74.57, H, 6.07, N, 5.12. Found: C, 74.86, H, 5.97, N, 5.06.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[C:26]([F:34])[CH:25]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:31](=[O:32])[CH2:30][C:27]2[CH:28]=[CH:29][C:24]([Br:23])=[CH:25][C:26]=2[F:34])=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Cc1ccc(Br)cc1F)Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Yield: 88.5 %

Procedure:
A suspension of 4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (668 mg, 2.146 mmol) in DCM (35 mL) was added to a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (500 mg, 2.146 mmol) in DCM (35 mL). HOBt (493 mg, 3.22 mmol), EDC (617 mg, 3.22 mmol) and Et3N (0.897 mL, 6.44 mmol) and the mixture was at 26° C. for 3 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=10/1). All fractions found to contain product by TLC (PE/EA=5/1, Rf 0.6) were combined and concentrated to yield a light yellow solid of N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2-fluorophenyl)acetamide (1 g, 1.900 mmol, 89.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.83-7.82 (d, J=2.8 Hz, 1H), 7.33-7.24 (m, 10H), 4.83 (s, 1H), 4.23-4.21 (m, 2H), 3.84-3.83 (m, 2H), 3.71-3.67 (m, 2H); ES-LCMS m/z 525.9 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1.C(=O)([O-])[O-].[Na+].[Na+].CCO>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CCOC(=O)c1c(Cl)c2cc(B(O)O)ccc2n1-c1ccc(OC(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(Cl)c2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)cc1
Temperature: 85 °C
Yield: 95 %

Procedure:
A stirred mixture of 3-chloro-5-(dihydroxyboryl)-1-(4-isopropoxyphenyl)-1H-indole-2-carboxylic acid ethyl ester (200 mg, 0.50 mmol; see step (b) above), 2-bromo-5-(trifluoromethyl)pyridine (170 mg, 0.75 mmol), sodium carbonate (2M in water, 0.75 mL, 1.5 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), EtOH (0.4 mL) and toluene (1.6 mL) was heated at 85° C. for 3 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, concentrated and purified by chromatography to give the sub-title compound (239 mg, 95%).
Reaction SMILES: S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].CN(C)[CH:13]=[CH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=1[N+:24]([O-])=O.[CH2:28](O)C.O>C1COCC1.ClCCl>[NH:24]1[C:16]2[C:15](=[CH:23][CH:22]=[C:18]([C:19]([O:21][CH3:28])=[O:20])[CH:17]=2)[CH:14]=[CH:13]1
Reactant: CCO
Reactant: CN(C)C=Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
Sodium dithionate (164.4 g; 16 equiv.) was added over a period of 20 minutes to a solution of 4-(2-(dimethylamino)vinyl)-3-nitrobenzoic acid (14 g; 1 equiv.) in a mixture of THF (42 ml), ethanol (42 ml) and water (140 ml). The reaction mixture was heated for 90 min. at reflux and then stirred for 12 hours at room temperature. When the conversion was complete, dichloromethane was added, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate. After removal of the solvent under reduced pressure, purification was carried out by column chromatography (silica gel, 10% ethyl acetate/hexane). Methyl 1H-indole-6-carboxylate (8 g; 40%) was obtained in the form of a solid.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:3].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH:14]=O.[CH2:23](O)[CH3:24]>O.[OH-].[Na+]>[O:3]=[C:2]([CH:1]=[CH:23][CH2:24][CH2:14][C:13]1[CH:12]=[C:11]([O:10][CH3:9])[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=1)[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCO
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC(=O)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CCC=CC(=O)CCC(=O)O)cc(OC)c1OC
Reaction time: 8 h

Procedure:
A solution of laevulinic acid (50 g, 0.43 mol) in water (200 ml) was added to a mixture of 3,4,5-trimethoxybenzaldehyde (85 g, 0.43 mol) in ethanol (150 ml) and sodium hydroxide solution (5%, 700 ml). The mixture was warmed with vigorous stirring until all the aldehyde had dissolved and was then poured onto ice (ca 2 Kg). It was then acidified to pH3-4 and left overnight. The crystalline material formed was filtered off, dried in vacuo and then recrystallised from ethanol to give pale yellow crystals (30.08 g), m.p. 187°-9°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH2:13](Br)[CH:14]=[CH2:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:9][C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[F:8])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1cc(Br)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1c(F)cc(Br)cc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-6-fluoro-2-nitrophenol (2 g, 8.49 mmol), allyl bromide (0.88 mL, 10.07 mmol) and K2CO3 (2.34 g, 16.98 mmol) in DMF (20 mL) was stirred at 45° C. overnight. Inorganic salts were filtered off, and the filtrate was concentrated to provide the crude product, which was directly used for next step without further purification. MS (DCI/NH3) m/z 245.92 (M+H)+; 1H NMR (400 MHz, DMSO-D6) δ ppm 4.70 (d, J=6.14 Hz, 2 H) 5.27 (d, J=10.43 Hz, 1 H) 5.37 (dd, J=17.18, 1.53 Hz, 1 H) 5.92–6.02 (m, 1 H) 8.03–8.06 (m, 2 H).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](O)=[O:11])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].S(Cl)([Cl:17])=O>C1C=CC=CC=1>[ClH:17].[C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([Cl:17])=[O:11])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]
Reactant: N=C(N)c1ccc(OCC(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cl
Product: N=C(N)c1ccc(OCC(=O)Cl)cc1

Procedure:
9.7 g of 4-amidinophenoxyacetic acid (M.p. 324° to 326° C) were suspended in 50 ml of anhydrous benzene, 29.7 of thionyl chloride were added and the whole was heated for 1 hour on the steam bath under reflux. After the reaction mixture had cooled, the solid product was filtered off with suction. 11.4 g of 4-amidinophenoxyacetyl chloride-hydrochloride melting at 142° - 143° C (with decomposition) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([F:10])=[CH:8][N:9]=1)[CH:5]=[O:6].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][O:6]2)[C:7]([F:10])=[CH:8][N:9]=1
Reactant: OCCO
Reactant: O=Cc1cc(Br)ncc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cnc(Br)cc1C1OCCO1

Procedure:
A mixture of 2-bromo-5-fluoroisonicotinaldehyde (495 mg, 2.43 mmol), ethylene glycol (0.27 mL, 4.85 mmol) and p-toluenesulfonic acid monohydrate (508 mg, 2.67 mmol) in toluene (13.5 mL) was refluxed for 4 hours. The mixture was concentrated and taken up in CH2Cl2, washed with 1 M NaOH, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (cyclohexane/EtOAc) to give INT 44.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[NH:4][C:5](C)=[C:6](CC)[CH:7]=1.BrC[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1.[CH2:24](N(CC)CC)C>C(#N)C>[C:17]1([CH2:24][NH:1][C:2]2[C:3](=[O:11])[NH:4][CH:5]=[CH:6][CH:7]=2)[C:16]2[C:21](=[CH:22][CH:23]=[CH:14][CH:15]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCc1cc(N)c(=O)[nH]c1C
Reactant: CCN(CC)CC
Solvent: CC#N
Product: O=c1[nH]cccc1NCc1cccc2ccccc12
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A mixture of 3-amino-5-ethyl-6-methyl-2-(1H)-pyridinone (3.0 g, 20 mmol), 2-bromomethylnapthalene (4.4 g, 20 mmol), triethylamine (2.0 g, 20 mmol) in acetonitrile (200 mL) was heated under reflux for 4 hours. The resultant mixture was allowed to cool to room temperature and concentrated under reduced pressure (15 torr). The residue was then subjected to column chromatography on silica gel (300 g, elution with methanol-chloroform, 5:95 v/v). Collection and concentration of appropriate fractions provided 2.4 g (42%) of the napthylmethylaminopyridone.
Reaction SMILES: [CH:1]([N:3]1[C:6](=[O:7])[CH:5]([NH:8][C:9](=[O:18])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]1[S:19][C:20](OC(=O)C)([CH3:22])[CH3:21])=[O:2]>C1C=CC=CC=1>[CH:1]([N:3]1[C:6](=[O:7])[CH:5]([NH:8][C:9](=[O:18])[CH2:10][O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:4]1[S:19][C:20]([CH3:22])=[CH2:21])=[O:2]
Reactant: CC(=O)OC(C)(C)SC1C(NC(=O)COc2ccccc2)C(=O)N1C=O
Solvent: c1ccccc1
Product: C=C(C)SC1C(NC(=O)COc2ccccc2)C(=O)N1C=O
Reaction time: 3 h

Procedure:
A solution of 0.051 g of 1-formyl-2-(2-acetyloxy-2-propyl-mercapto)-3-(N-phenyloxyacetyl-amino)-azetidin-4-one in 3 ml of anhydrous benzene is treated with 0.13 g of tristriphenyl-phosphine-rhodium chloride and boiled for 3 hours under reflux. The initially red solution turns brown, with a small quantity of a precipitate forming. After cooling, the precipitate is filtered off and the filtrate is evaporated under reduced pressure. The residue is chromatographed on 5 g of acid-washed silica gel, with fractions of 5 ml each being collected. The elution is carried out with 10 ml of benzene, 30 ml of a 9:1-, 25 ml of a 4:1- and 10 ml of a 1:1-mixture of benzene and ethyl acetate and then with 25 ml of ethyl acetate. Fractions 2-6 yield a rhodium complex having a strong CO-absorption at 5.18μ in the infra-red absorption spectrum. A small quantity of 1-formyl-2-isopropenylmercapto-3-(N-phenyloxyacetyl-amino)-azetidin-4-one can be isolated from fractions 10-12, while fractions 15-17 yield the 2-isopropenylmercapto-3-(N-phenyloxyacetyl-amino)-azetidin-4-one of the formula ##STR23## in an amorphous form. The product is obtained in crystalline form when the solution of the eluate is filtered through 0.5 g of acid-washed silica gel and the product is eluted with a 1:1-mixture of benzene and ethyl acetate, m.p. 156°-158°; [α]D20 = -70° ± 2° (c = 0.665 in chloroform); infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.07μ, 5.65μ, 5.96μ, 6.29μ, 6.59μ. 6.74μ, 8.19μ, 9.25μ and 9.92μ.
Reaction SMILES: [IH:1].CS[C:4]1[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]=1.C(O)C.O.[NH2:15][NH2:16]>CCOCC>[IH:1].[NH:15]([C:4]1[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]=1)[NH2:16]
Reactant: NN
Reactant: CSC1=NCCCCN1
Agent: I
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: NNC1=NCCCCN1
Temperature: -10 °C

Procedure:
A 40.8 gm. (0.15 mole) portion of 2-methylthio-4,5,6,7-tetrahydro-1H-1,3-diazepine hydroiodide in 150 ml. of ethanol is treated with 10 ml. (0.2 mole) of hydrazine hydrate. The solution is stirred at reflux for 3 hours, clarified while hot and then cooled at -10°C. overnight. A 200 ml. portion of ether is added and the mixture is cooled at -10°C. The precipitate is collected, washed with ether and dried at 60°C. under reduced pressure. Yield 20.5 gm., melting point 133°-135°C. Analysis calculated for: C5H12N4 . HI: C, 23.45; H, 5.12; N, 21.88; I, 49.56. Found: C, 22.85; H, 4.96; N, 21.90; I, 50.35.
Reaction SMILES: [F:1][C:2]1[C:3]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#N.[OH-:15].[Na+].Cl.C[OH:19]>>[F:1][C:2]1[C:3]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]([OH:19])=[O:15]
Reactant: N#Cc1cccc(F)c1-n1nccn1
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cccc(F)c1-n1nccn1
Temperature: 25 °C
Yield: 18 %

Procedure:
To 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzonitrile (1.5 g, 8.0 mmol) in MeOH (30 mL) was added 2M aq. NaOH (10 mL). The reaction was heated at reflux for 15 h, then cooled to rt, acidified with 1 N aq. HCl to pH 1 and extracted with CH2Cl2 (2×). The combined organics were washed with brine and dried (Na2SO4). Purification via Agilent (Reverse-Phase HPLC, basic conditions) gave the title compound (290 mg, 18%). 1H NMR (CDCl3): 7.90 (s, 2H), 7.89-7.85 (m, 1H), 7.63-7.56 (m, 1H), 7.50-7.44 (m, 1H) and 3-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 53, 140 mg, 8%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[O:5][C:6](=[O:17])[C:7]2[C:13]([OH:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:8]=2[CH:9]=1)#[N:2].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C1(C)C=CC=CC=1>CN(C)C=O>[Si:23]([O:14][C:13]1[C:7]2[C:6](=[O:17])[O:5][C:4]([CH2:3][C:1]#[N:2])=[CH:9][C:8]=2[CH:10]=[C:11]([O:15][CH3:16])[CH:12]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: COc1cc(O)c2c(=O)oc(CC#N)cc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(O[Si](C)(C)C(C)(C)C)c2c(=O)oc(CC#N)cc2c1
Reaction time: 2 h
Yield: 93.4 %

Procedure:
2.70 g (11.68 mmol) of the 3-cyanomethyl-8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran obtained in Example 3 was suspended in 25 ml of dimethylformamide. 1.59 g (23.4 mmol) of imidazole and 2.82 g (18.7 mmol) of tert-butyldimethylsilyl chloride were successively added thereto under cooling with ice, and the resulting mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture was mixed with toluene, washed once with 50 ml of a 10% aqueous solution of sodium chloride, and washed twice with 50 ml portions of a 20% aqueous solution of sodium chloride. The toluene layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried in vacuo. The resulting residue was recrystallized from 20 ml of ethanol to obtain 3.77 g of the title compound in a 93% yield.