Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:17])[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](=O)[CH2:26]Br.O>CN(C=O)C>[C:12]([CH:9]1[CH2:8][CH2:7][C:6]2[NH:5][C:4](=[O:17])[N:3]3[CH:26]=[C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[F:18])[N:1]=[C:2]3[C:11]=2[CH2:10]1)([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C(CBr)c1ccccc1F
Reactant: CCOC(=O)C1CCc2[nH]c(=O)nc(N)c2C1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1

Procedure:
A solution of 4-Amino-6-carboethoxy-5,6,7,8-tetrahydro-2(1H)-quinazolinone (262 mg) and 2'-fluoro-bromoacetophenone (217 mg) in dry DMF (10 mL) was refluxed under nitrogen for 1.5 h. The solution was cooled and 40 mL water is added. The precipitate was collected and washed successively with 10 mL of methanol and 20 mL hot ethyl acetate to yield 9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (Compound 1), m.p. 257°-277° C.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:39])=[C:5]([C:30]([O:37]C)=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][C:7]1[C:8]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[C:9]([CH:21]=[CH:22][CH:23]=1)[C:10]([NH:12][C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:11].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(=O)([O-])O.[Na+]>C(#N)C.O>[CH3:34][O:33][C:32]1[C:3](=[O:2])[C:4]([CH3:39])=[C:5]([CH2:6][C:7]2[C:8]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[C:9]([CH:21]=[CH:22][CH:23]=2)[C:10]([NH:12][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])=[O:11])[C:30](=[O:37])[C:31]=1[O:35][CH3:36]
Reactant: COc1c(C)c(Cc2cccc(C(=O)N[C@@H](C)c3ccccc3)c2-c2ccncc2)c(OC)c(OC)c1OC
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N[C@@H](C)c3ccccc3)c2-c2ccncc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
(S)-N-[3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoyl]-1-phenylethylamine (64 mg, 0.1216 mmol) was dissolved in a mixed solvent of acetonitrile (9 ml) and water (3 ml), then CAN (166 mg, 0.3029 mmol) was added thereto at room temperature and the mixture was stirred for 3 hours. The reaction solution was poured into water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:3) to give the title compound (30 mg, 0.0604 mmol, 50%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: C1CNCCNC1
Reactant: Brc1ccccn1
Solvent: O
Product: c1ccc(N2CCCNCC2)nc1
Temperature: 100 °C

Procedure:
A mixture of 2-bromopyridine and 12 g of homopiperazine is heated at 100° C. for 6 hours. 50 ml of water are added to the reaction mixture and the resulting mixture is extracted with EtOAc, the organic phase is washed with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 1.28 g of the expected product are obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:15])=[C:4]([C:8]([CH3:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:16]([O-])([O-])=O.[K+].[K+].IC>CN(C)C=O.O>[Br:1][C:2]1[C:3]([F:15])=[C:4]([C:8]([CH3:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: Cc1c([N+](=O)[O-])cc(Br)c(F)c1C(=O)O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c([N+](=O)[O-])cc(Br)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 3-bromo-2-fluoro-6-methyl-5-nitrobenzoic acid (2.41 g, 8.67 mmol) in N,N-Dimethylformamide (25 ml) at room temperature and under nitrogen was added K2CO3 (2.4 g, 17.34 mmol) followed by iodomethane (0.7 ml, 11.27 mmol). The reaction mixture was stirred at room temperature for 2 hours before being diluted with deionized water (100 ml) and extracted with EtOAc (3×50 ml). The combined organic phases were washed with saturated NaHCO3(aq) (50 ml) and then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified twice by FCC (50 g silica, Isolute cartridge, gradient of eluents; 98:2 Heptane:EtOAc to 9:1 Heptane:EtOAc) to give 2.43 g (89%) of methyl 3-bromo-2-fluoro-6-methyl-5-nitrobenzoate as a white solid. LC-MS 99%, 2.18 min (3 minute LC-MS method), m/z=no ionization, 1H NMR (500 MHz, Chloroform-d) δ ppm 8.22 (d, J=6.2 Hz, 1H), 4.00 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:14]([CH3:15])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[C:10]=2[N:23]=1)C.[Li+].[BH4-]>C1COCC1>[CH3:15][N:14]1[CH2:13][CH2:12][NH:11][C:10]2[N:23]=[C:6]([CH2:5][CH2:4][OH:3])[CH:7]=[CH:8][C:9]1=2
Reactant: CCOC(=O)Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCN2C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCNc2nc(CCO)ccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 6-(2-ethoxy-2-oxoethyl)-1-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate 1.05 g, 3.13 mmol)) in dry THF (15 mL) at room temperature was added a solution of LiBH4 (2.0 M in THF, 1.88 mL), and the resulting mixture was heated to reflux. After 16 hours the mixture was cooled to 0° C. and carefully quenched with water (20 mL). After 10 minutes, the mixture was extracted three times with ethyl acetate. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. This residue was dissolved in CH2Cl2 (3 mL), and to this solution was added 4 M HCl in dioxane (6 mL) all at once at room temp. After 4 hours, the mixture was concentrated under reduced pressure to get the crude product, which was chromatographed on silica gel (eluent: 98/2/0.5 dichloromethane/methanol/-ammonium hydroxide) to afford the desired product as a gray solid. (390 mg) H NMR (400 MHz, CDCl3) δ 2.73 (t, 2H), 2.72 (s, 3H), 3.20 (t, 2H), 3.58(m, 2H), 3.89 (t, 2H), 6.36 (d, 1H), 6.58(d, 2H).
Reaction SMILES: O=[C:2]([CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>[Pt]>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][CH:2]([CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:19][CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)C(=O)CCCCCCCC(=O)O
Agent: [Pt]
Product: CC(C)C(CCCCCCCC(=O)O)NCc1ccc(F)cc1

Procedure:
Using the procedure of example I step D and starting from 9-oxo 10-methyl undecanoic acid and para fluorobenzylamine then hydrogenating in the presence of a platinum catalyst dl 9-(para fluorobenzylamino) 10-methyl undecanoic acid is obtained melting at 78°-82° after recrystallisation from acetonitrile.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([N:7]1[C:20]2[CH:19]=[C:18]3[C:21]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:22]4[C:27]([C:17]3=[CH:16][C:15]=2[C:14]([CH3:33])([CH3:32])[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:6].[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[C:34]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:5][CH3:6])[C:20]1[CH:19]=[C:18]3[C:21]([CH2:28][CH3:29])([CH2:30][CH3:31])[C:22]4[C:27]([C:17]3=[CH:16][C:15]=1[C:14]2([CH3:33])[CH3:32])=[CH:26][CH:25]=[CH:24][CH:23]=4)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CCN1c2ccccc2C(C)(C)c2cc3c(cc21)C(CC)(CC)c1ccccc1-3
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCN1c2ccc(C(C)=O)cc2C(C)(C)c2cc3c(cc21)C(CC)(CC)c1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (3.43 g, 25.6 mmol) was slowly added into a dichloromethane solution (80 mL) in which were dissolved 11,13,13-triethyl-6,6-dimethyl-11,13-dihydro-6H-11-aza-indeno[2,1-b]anthracene (6.80 g, 20.0 mmol) and acetyl chloride (1.83 mL, 25.7 mmol) at 0° C. under nitrogen atmosphere. After stirring at room temperature overnight, the reaction mixture was poured into ice-water. The product was extracted twice with dichloromethane. The combined organic layer was washed with brine, and dried over MgSO4. Dichloromethane was removed under high vacuum and the product thus obtained was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[N+:17]([O-])(O)=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:17][C:9](=[O:11])[CH2:8]2
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1cccc(F)c1
Agent: O=S(=O)(O)O
Product: O=C1Cc2cc(F)ccc2N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To the solution of 3-fluorophenylacetic acid (1.23 g, 8 mmol) in concentrated H2SO4 (2.0 mL, 40 mmol) at 0° C. was added HNO3 (0.374 mL, 8 mmol) slowly. The resulting reaction mixture was stirred under argon for 2 h at 0° C., and poured into ice-water. The white solid was precipitated, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with brine, dried with Na2SO4, and concentrated. The crude (5-fluoro-2-nitro-phenyl)-acetic acid was dissolved in acetic acid. To the solution was added iron power (1.79 g, 32 mmol). The reaction mixture was stirred and heated at reflux for 2 h. Then the mixture was concentrated in vacuo. The residue was extracted with ethyl acetate, and The organic layer was separated, washed by aqueous HCl (1N), brine, dried over Na2SO4, concentrated in vacuo to give the desired product (1 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:28]=1[C:29](Cl)=[O:30].IC1C=CC=CC=1C(NCCN1C(=O)CC(=O)NC2C3C(C=CC1=2)=CC=CC=3)=O>>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:28]=1[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:30]
Reactant: COc1cccc(C)c1C(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Product: COc1cccc(C)c1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 61 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2-methoxy-6-methylbenzoyl chloride, the title compound (yield 61%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH:1]([C:3]1[C:8]2[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C:10]=3[O:20][C:7]=2[C:6]([O:21][CH3:22])=[CH:5][CH:4]=1)=[O:2].S(=O)(=O)([OH:25])N.Cl([O-])=O.[Na+]>O.CC(C)=O>[CH2:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C:9]2[C:8]3[C:7](=[C:6]([O:21][CH3:22])[CH:5]=[CH:4][C:3]=3[C:1]([OH:25])=[O:2])[O:20][C:10]=2[CH2:11]1)=[O:16])[CH3:19]
Reactant: NS(=O)(=O)O
Reactant: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C=O)c23)C1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)O)c23)C1
Yield: 41 %

Procedure:
Ethyl 5-formyl-8-methoxy-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (from step 6) (0.310 g, 1.02 mmol) was taken in acetone water mixture. To this was added sulphamic acid (0.148 g, 1.53 mmol) and sodium chlorite (0.157 g, 1.73 mmol) and stirred for half an hour. After removing acetone under diminished pressure and dilution with water, it yielded 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylic acid (41%) which was filtered out, washed with water and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:13])=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[CH:9]=[O:10])[CH3:2].C1(=O)O[CH2:17][CH2:16][O:15]1>C1(C)C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4]1[C:5]([O:13][CH2:17][CH2:16][OH:15])=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[CH:9]=[O:10])[CH3:2]
Reactant: CCOc1cc(C=O)c(F)cc1O
Reactant: O=C1OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: Cc1ccccc1
Product: CCOc1cc(C=O)c(F)cc1OCCO
Temperature: 25 °C
Yield: 90.8 %

Procedure:
The 5-ethoxy-2-fluoro-4-hydroxy-benzaldehyde (9.15 g) described in example 1.3 was dissolved in toluene (80 ml). Ethylene carbonate (5.25 g) and tetrabutylammonium iodide (1.83 g) were added and the mixture was heated to reflux for 22 h. The mixture was cooled to room temperature and filtered over a plug of silica gel. The product was eluted with hexane/ethyl acetate. The solvent was evaporated and the solid was washed with hot hexane to give 10.3 g of 5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-benzaldehyde as a slightly orange solid. MS: 228 ([M]+).
Reaction SMILES: C(OC(C)(C)C)(=O)/C=C/C.[CH3:11][C@H:12]([NH:19][C@H:20]([C:29]1C=CC=C[CH:30]=1)[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N([C@@H](C)C1C=CC=CC=1)[C@@H](C=CC)CC(OC(C)(C)C)=O)C=C.CC(C)C=CC(OC(C)(C)C)=O.C(N([C@@H](C)C1C=CC=CC=1)[C@@H](C=CC1C=CC=CC=1)CC(OC(C)(C)C)=O)C=C>C(Cl)(Cl)Cl>[CH3:11][C@H:12]([NH:19][C@@H:20]([CH2:29][CH3:30])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](N[C@@H](CC(=O)OC(C)(C)C)c1ccccc1)c1ccccc1
Agent: C/C=C/C(=O)OC(C)(C)C
Agent: C=CCN([C@@H](C=CC)CC(=O)OC(C)(C)C)[C@@H](C)c1ccccc1
Agent: C=CCN([C@@H](C=Cc1ccccc1)CC(=O)OC(C)(C)C)[C@@H](C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC[C@@H](CC(=O)OC(C)(C)C)N[C@@H](C)c1ccccc1

Procedure:
The title compound (31) was prepared from compound (10) of Example 3 using the above-described procedure. [α]D21 -54.0 (c 1.81, CHCl3); νmax (CHCl3)/cm-1 1724 s (C=O); δH (300 MHz; CDCl3) 7.36-7.20 (5H, m, Ph), 3.91 (1H, q, J=6.5, PhCHCH3), 2.68 (1H, m, NCHCH2), 2.39, 2.28 (2H, ABX system, JAB =14.3, JAX =5.7, JBX =5.5, CH2CO), 1.47 (9H, s, (CH3)3C), 1.41 (2H, m, CH3CH2), 1.34 (3H, d, J=6.5, PhCHCH3), 0.85 (3H, t, J=7.3, CH3CH2); δC (50 MHz; CDCl3) 172.19 (C=O), 146.44, (Ph:Cipso), 128.53, 126.92 (Ph:Cortho, Cmeta), 126.84 (Ph:Cpara), 80.23 (C(CH3)3), 55.01, 53.71 (CHN), 39.10 (CH2CO), 28.04 (C(CH3)3), 27.78 (CH3CH2), 24.80 (NCHCH3), 10.24 (CH3CH2); m/z (CI) 278 (MH+, 100%), 248 (5), 222 (30), 192 (12), 162 (15), 105 (20); (Found: C, 73.84; H, 10.11; N, 4.93. C17H27NO2 requires C, 73.61; H, 9.81; N, 5.05%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([NH:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Reactant: NCCN1CCOCC1
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(NCCN4CCOCC4)nc32)c(=O)[nH]c1=O

Procedure:
The subtitle product was prepared from the product of example 44 step (viii) (0.225 g) and 4-(2-aminoethyl)morpholine (0.38 ml) according to the method of example 51 step (i). Purification was by precipitation using diethyl ether with filtration to give the subtitle product as yellow solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[S:3]([CH2:5][C:6]([NH:8][CH:9]1[C:31](=[O:32])[N:11]2[C:12]([C:24]([O:26]C(C)(C)C)=[O:25])=[C:13]([CH:16]([S:18][C:19]3[NH:23][N:22]=[N:21][N:20]=3)[CH3:17])[CH2:14][S:15][C@H:10]12)=[O:7])=[O:4].CCOCC>FC(F)(F)C(O)=O>[F:34][C:2]([F:1])([F:33])[S:3]([CH2:5][C:6]([NH:8][CH:9]1[C:31](=[O:32])[N:11]2[C:12]([C:24]([OH:26])=[O:25])=[C:13]([CH:16]([S:18][C:19]3[NH:23][N:22]=[N:21][N:20]=3)[CH3:17])[CH2:14][S:15][C@H:10]12)=[O:7])=[O:4]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)CS(=O)C(F)(F)F)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)C(F)(F)F)[C@H]2SC1
Reaction time: 0.08 h

Procedure:
To a solution of 1.54 g (0.004 mol) of 7-amino-3-(1-methyl-1,2,3,4-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, t-butyl ester and 0.825 g (0.004 mol) of dicyclohexylcarbodiimide in 50 ml of benzene was added 0.704 g (0.004 mol) of trifluoromethylsulfinylacetic acid. The reaction mixture was stirred at 25° for 2 hr., then it was filtered and adsorbed onto 4 g of silica gel. Chromatography on 100 g of silica gel with 50:50 benzene-ethyl acetate gave 1.55 g (69 percent) of 7-trifluoromethylsulfinylacetamido-3-(1-methyl-1,2,3,4-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, t-butyl ester as a white foam. The ester was dissolved in 9 ml of trifluoroacetic acid and stirred at 25° for 5 minutes, then added dropwise to 200 ml of ether. The precipitate was collected, dissolved in 5 percent sodium bicarbonate and the solution was diluted to 150 ml. After extraction with ethyl acetate the aqueous phase was acidified to pH 1.5 and extracted thrice more with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated to 35 ml, to which residue (the free acid) was added a solution of 1.5 g of 30 percent sodium 2-ethylhexanoate in isopropanol followed by 200 ml of ether. The precipitated salt was collected, reprecipitated from methanol-ether and dried in vacuo to give 0.680 g of product.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].C1(N=C=NC2CCCCC2)CCCCC1.CN(C)C=[O:35]>>[OH:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:1].[CH:11]1[C:16]([OH:35])=[CH:8][C:7]2[O:3][C:2]([CH:4]=[CH:5][C:6]=2[CH:10]=1)=[O:1]
Reactant: CN(C)C=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Product: O=c1ccc2ccc(O)cc2o1
Temperature: 7 °C
Reaction time: 4 h

Procedure:
A reaction mixture was formed by dissolving in 10 ml of dimethylformamide 100 mg of unbelliferone, 167 mg of biotin, and 141 mg of dicyclohexyl carbodiimide. The reaction mixture was incubated at -18° C. for about 4 hours, then overnight at 7° C. and allowed to stand at room temperature for from 3 to 4 hours. An additional 141 mg of dicyclohexylcarbodiimide was added and the reaction mixture was stirred at 7° C. for from 3 to 4 hours and allowed to stand at room temperature overnight. The resulting precipitate was filtered off and discarded. To the filtrate was added 75 ml of ice water, and the resulting mixture was incubated at 0° C. for 1 hour. The precipitate which resulted was filtered off and discarded. The filtrate was evaporated to dryness and the residue dissolved in from 3 to 4 ml of methylene chloride. To the resulting solution was added 5 ml of diethylether. The resulting precipitate which comprised the biotin-umbelligerone conjugate was filtered off, dried, and stored at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.CC(C)([O-])C.[K+].Cl[CH2:16][CH2:17][CH2:18][N:19]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C>[N:19]1([CH2:18][CH2:17][CH2:16][S:8][C:5]2[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: S=c1ncc(Cl)c[nH]1
Reactant: ClCCCN1CCCCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cnc(SCCCN2CCCCCCC2)nc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
5-Chloropyrimidine-2-thione (2 mmol) and potassium tert-butoxide (2 mmol) was stirred together in DMF (20 ml) for 5 min at room temperature before 1-(3-chloropropyl)perhydroazocine (2 mmol) was added. The mixture was stirred for 2 days at room temperature and for 2 hours at 80° C. The solution was evaporated, the residue triturated with water, extracted with chloroform and the dried (MgSO4) chloroform solution evaporated. The oily product which remained (0.47 g) was the title compound; yield 45% 1H NMR (CDCl3): 1.3-2.8 (9×CH2), 3.20 (SCH2), 8.40 (H-4, H-6). The compound was further characterized as a solid by conversion into its HCl salt using HCl in ethanol; m.p. 154° C. (acetone).
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[F:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][CH2:20][C:21]2[C:22]([NH:31][CH:32]([CH3:34])[CH3:33])=[CH:23][C:24]([N:27]([O:29][CH3:30])[CH3:28])=[N:25][CH:26]=2)=[C:12]([CH3:35])[CH:11]=1.CCN(CC)CC>O1CCOCC1>[F:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([N:19]2[CH2:20][C:21]3[CH:26]=[N:25][C:24]([N:27]([O:29][CH3:30])[CH3:28])=[CH:23][C:22]=3[N:31]([CH:32]([CH3:33])[CH3:34])[C:4]2=[O:3])=[C:12]([CH3:35])[CH:11]=1
Reactant: CON(C)c1cc(NC(C)C)c(CNc2cc([N+](=O)[O-])c(F)cc2C)cn1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CON(C)c1cc2c(cn1)CN(c1cc([N+](=O)[O-])c(F)cc1C)C(=O)N2C(C)C
Yield: 70.2 %

Procedure:
Using the procedure of Example A4 step 3, diphosgene (1.3 g, 6.4 mmol), 5-((4-fluoro-2-methyl-5-nitrophenylamino)methyl)-N4-isopropyl-N2-methoxy-N2-methylpyridine-2,4-diamine (2.0 g, 5.3 mmol) and Et3N (2.2 g, 21.2 mmol) were reacted in dioxane to give 3-(4-fluoro-2-methyl-5-nitrophenyl)-1-isopropyl-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (1.5 g, 70% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.18 (d, J=7.2 Hz, 1 H), 7.94 (s, 1 H), 7.55 (d, J=12.4 Hz, 1 H), 6.68 (s, 1 H), 4.77 (d, J=13.6 Hz, 1 H), 4.45-4.37 (m, 2 H), 3.71 (s, 3 H), 3.13 (s, 3 H), 2.14 (s, 3 H), 1.46 (t, J=6.4 Hz, 6H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:17]=[C:16]([NH:18][CH:19]=[O:20])[S:15][N:14]=1)[C:10]([OH:12])=O.[NH2:21][CH:22]1[C:40](=[O:41])[N:24]2[C:25]([C:37]([OH:39])=[O:38])=[C:26]([CH:29]([S:31][C:32]3[NH:36][N:35]=[N:34][N:33]=3)[CH3:30])[CH2:27][S:28][C@H:23]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:17]=[C:16]([NH:18][CH:19]=[O:20])[S:15][N:14]=1)[C:10]([NH:21][CH:22]1[C:40](=[O:41])[N:24]2[C:25]([C:37]([OH:39])=[O:38])=[C:26]([CH:29]([S:31][C:32]3[NH:33][N:34]=[N:35][N:36]=3)[CH3:30])[CH2:27][S:28][C@H:23]12)=[O:12]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1nsc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1nsc(NC=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
A mixture of N,N-dimethylformamide (6 ml) and phosphorus oxychloride (918 mg) was stirred for 30 minutes at ambient temperature. To the mixture were added methylene chloride (6 ml) and 2-methoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (1.1 g) at -15° to -10° C., followed by stirring for 30 minutes at the same temperature. A mixture of 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (1.97 g) and trimethylsilylacetamide (6 g) in methylene chloride (60 ml) was warmed to make a clear solution. The solution was cooled to -15° C. and added to the above obtained solution. The reaction mixture was stirred for an hour at 0° C. and poured into a cold aqueous solution of sodium bicarbonate. The aqueous layer was separated, adjusted to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give a crude product of the title compound (2.75 g). The crude material was dissolved in an aqueous solution of sodium bicarbonate and reprecipitated with diluted hydrochloride acid to give the pure title compound (1.5 g), mp. 170° to 175° C. (dec.).