Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].C([Li])(C)(C)C.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[OH:33][C:30]1([C:2]2[C:3](=[O:12])[NH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]1
Reactant: O=c1[nH]c2ccccc2cc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc3ccccc3[nH]c2=O)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A flask was charged with 3-bromoquinolin-2(1H)-one (U.S. Pat. Appl. Publ. 2002, U.S. 2002099208 A1; Payack, J. F. et al. J. Org. Chem. 2005, 70, 1, 175.) (1.0 g, 4.46 mmol) and sodium hydride (118 mg, 4.91 mmol). The solids were dissolved in tetrahydrofuran (30 mL), stirred for 15 min, and cooled to −78° C. The solution was treated with tert-butyllithium (1.7 M in pentane, 5.25 mL, 8.93 mmol) and stirred for 1 h. To this was added N-tert-butoxycarbonyl-4-piperidone (889 mg, 1.0 equiv). The ice bath was removed and stirring continued for 1 h. The reaction was quenched by addition of saturated ammonium chloride. The reaction was diluted with diethyl ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. The resulting oil was triturated with diethyl ether to give a white solid which was filtered, washed with diethyl ether, and air dried to give 430 mg (28%) as a white powder. 1H-NMR (CDCl3, 500 MHz) δ 1.48 (s, 9H), 1.57 (bs, 2H), 1.87 (m, 2H), 2.13 (m, 2H), 3.37 (m, 2H), 4.06 (m, 2H), 7.28 (m, 2H), 7.53 (m, 2H), 7.60 (m, 1H), 7.69 (s, 1H). Mass spec.: 367.35 (MNa)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]4[CH:19]5[CH:23]([CH2:24][C:12]([C:13]=34)=[CH:11]2)[N:22]([CH3:25])[CH2:21][CH:20]5[C:26](OC)=[O:27])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>CO>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]4[CH:19]5[CH:23]([CH2:24][C:12]([C:13]=34)=[CH:11]2)[N:22]([CH3:25])[CH2:21][CH:20]5[CH2:26][OH:27])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CN(C)C2Cc3cn(S(=O)(=O)c4ccccc4)c4cccc(c34)C12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC(CO)C2c3cccc4c3c(cn4S(=O)(=O)c3ccccc3)CC21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a stirred solution of the 9-methyl ester (Example 14) (0.365 g) in dry methanol (4 cm3) under anhydrous conditions was added sodium borohydride (0.252 g) causing vigorous effervescence. After 2 hours further sodium borohydride (0.067 g) was added. After the initial effervescence had subsided the reaction was heated to 60° C. Reaction was indicated to be complete and after 4 hours water (4 cm3) was carefully added and the cloudy mixture allowed to cool to room temperature. The product was extracted from the aqueous solution with chloroform, the combined extract washed with water (50 cm3), dried and evaporated under vacuum to yield the title compound as a yellow-white foam, m.p. 124°-127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:32]4[CH2:37][CH2:36][CH:35]([N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH2:34][CH2:33]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: C1CC(N2CCOCC2)CCN1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC(N2CCOCC2)CC1
Yield: 43 %

Procedure:
4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl}benzoic acid (70 mg) was reacted with 4-piperidin-4-yl-morpholine as in General Procedure 8 to give the title compound as a light yellow foam (43% yield). M.p. (foam), LCMS: m/z=600.14 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.42-1.58 (m, 2H), 1.72-1.94 (m, 2H), 2.35-2.45 (m, 1H), 2.52-2.58 (m, 4H), 2.86-3.03 (m, 2H), 3.47-3.53 (m, 2H), 3.63-3.74 (m, 6H), 3.88-3.96 (m, 1H), 4.58 (s, 2H), 5.12 (s, 1H), 6.59 (d, J=8.3 Hz, 1H), 7.32-7.49 (m, 5H), 7.64 (d, J=8.3 Hz, 1H), 7.74 (d, J=1.76 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9]Cl)=[C:4]([CH3:11])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][NH:19][C@@H:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1.O>CCO.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][N:19]([CH3:18])[C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH2:21]2)=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1nc(Cl)nc(Cl)c1CCl
Reactant: CN[C@H]1CCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1nc(Cl)nc(Cl)c1CN(C)[C@H]1CCCc2ccccc21
Temperature: 0 °C

Procedure:
To a flask containing 2,4-dichloro-5-chloromethyl-6-methyl-pyrimidine (107 mg, 0.51 mmol) in absolute EtOH (10 mL) is added K2CO3 (70 mg, 1.0 eq., 0.51 mmol) and the reaction is cooled to 0° C. with an ice bath. (1S)-Methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (82 mg, 1.0 equiv, 0.51mmol) in 1.0 mL of EtOH is added via syringe in one portion and allowed to warm to ambient temperature over 3 h. Water (50 mL) and EtOAc (50 mL) is added and the EtOAc layer is washed with water (100 mL) and brine (50 mL) and dried over Na2SO4. Concentration and vacuum drying affords the title compound as a yellow gum. [mass expected (336.26); mass found (336.30)]
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:21](=[O:23])[CH3:22]>C1COCC1>[Cl:1][C:2]1[C:11]([CH:21]([OH:23])[CH3:22])=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Fc1cccc2ccc(Cl)nc12
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1cc2cccc(F)c2nc1Cl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
2-Chloro-8-fluoroquinoline (182 mg, 1.0 mmol) was dissolved in THF (2 mL) and cooled to −78° C. To this solution was added Lithium diisopropylamide (1M solution in THF, 1.1 mL, 1.1 mmol, 1.1 eq). The reaction was allowed to stir at −78° C. for 20 min, after which time acetaldehyde (113 μl, 2.0 mmol, 2 eq.) was added via syringe. After 30 minutes, the reaction was quenched with water and diluted with ethyl acetate. The layers were separated and washed with brine. The crude reaction mixture was purified by column chromatography (8:2 hexanes:ethyl acetate) to afford 1-(2-chloro-8-fluoroquinolin-3-yl)ethanol. 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (br s, 1H), 7.64 (td, J=7.8, 5.1 Hz, 1H), 7.41 (ddd, J=10.2, 7.4, 1.2 Hz, 1H), 5.39 (qdd, J=6.3, 3.9, 0.8 Hz, 1H), 2.22 (d, J=3.9 Hz, 1H), 1.62 (d, J=6.3 Hz, 3H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[N:20][C:21]2[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([CH:29]=2)[C:26]([OH:28])=[O:27])=[CH:15][CH:14]=1)=[N+:2]=[N-:3].[C:31](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]=[N:20][C:21]2[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([CH:29]=2)[C:26]([O:28][CH3:31])=[O:27])=[CH:17][CH:18]=1)=[N+:2]=[N-:3]
Reactant: O=C([O-])[O-]
Reactant: [N-]=[N+]=NCCCCCCCCOc1ccc(N=Nc2ccc(O)c(C(=O)O)c2)cc1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1cc(N=Nc2ccc(OCCCCCCCCN=[N+]=[N-])cc2)ccc1O
Temperature: 25 °C
Yield: 50.5 %

Procedure:
To a stirred solution of 5-((4-(8-azidooctyloxy)phenyl)diazenyl)-2-hydroxybenzoic acid (400 mg, 0.97 mmol) in acetone (20 mL) was added powdered anhydrous potassium carbonate (270 mg, 1.94 mmol). Dimethyl sulfate (92 mg, 0.97 mmol) was then added dropwise at room temperature. The reaction mixture was heated at reflux for 20 min and then allowed to cool to ambient temperature. Volatiles were removed in vacuo, the residue taken up in EtOAc (40 mL), the solution washed with water (2×20 mL), brine, dried over Na2SO4, and filtered. Volatiles were removed in vacuo and the residue subjected to column chromatography on silica gel 60 (230-400 mesh) using EtOAc and hexanes (95:5) as the elutant to give 210 mg (0.49 mmol, 50%) of the product as a yellow solid, mp 58-60° C. 1H NMR (500 MHz, CDCl3) δ 1.39-1.51 (m, 8H), 1.64 (qt, 2H), 1.83 (qt, 2H), 3.28 (t, J=Hz, 2H), 4.02 (s, 3H), 4.05 (t, J=6.5 Hz, 2H), 7.88 (d, J=Hz, 2H), 8.07 (dd, J=Hz, 2.5 Hz, 1H), 8.42 (d, J=2.5 Hz, 1H), 11.06 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 25.9, 26.7, 28.8, 29.1, 29.2, 51.5, 52.5, 68.2, 112.4, 114.7, 118.3, 124.5, 126.0, 128.7, 145.5, 146.7, 161.5, 163.3, 170.3; HRMS (ESI) calculated for C22H28N5O4 (M+H)+426.2135, observed 426.2141.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[N:4][CH:3]=1.[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([O:22][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[N:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H]1CNCCN1c1cncc(Cl)n1
Reactant: OCc1ccccc1
Solvent: CN(C)C=O
Product: C[C@H]1CNCCN1c1cncc(OCc2ccccc2)n1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To a solution of (2S)-1-(6-chloro-2-pyrazinyl)-2-methylpiperazine (prepared in step 2 above; 0.16 g, 0.72 mmol) and benzyl alcohol (0.12 g, 1.1 mmol) in DMF (4 mL) was Na-t-BuO (0.14 g, 1.4 mmol) added and the mixture was stirred at 150° C. overnight. The solvent was evaporated off under reduced pressure and the residue taken up between CHCl3/H2O. The organic phase was concentrated and the crude product was purified by preparative C18-HPLC using acetonitrile/H2O/HOAc with UV detection at 254 nm. Yield: 1 mg (0.4%). MS m/z 284 (M)+. HRMS m/z calcd for C16H20N4O (M)+ 284.1637, found 284.1640.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:18][CH:15]2[CH2:17][CH2:16]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Reactant: NC1CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(Cl)nc(NCCO)nc1NC1CC1

Procedure:
In analogy to the procedure described in example 38b, 4,6-dichloro-2-(2-hydroxy-ethyl-amino)-pyrimidine-5-carbonitrile was treated with cyclopropylamine in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-chloro-6-cyclopropylamino-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=254.
Reaction SMILES: [C:1]([CH2:13][C:14]([O:16]CC)=O)(=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH3:19][NH:20][C:21]([NH2:23])=[O:22].C(OCC)(=O)C>C1C2C(=CC=CC=2)CCC1>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([C:1]2[NH:23][C:21](=[O:22])[N:20]([CH3:19])[C:14](=[O:16])[CH:13]=2)[CH:11]=[CH:10][C:7]=1[O:8][CH3:9]
Reactant: CNC(N)=O
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Solvent: CCOC(C)=O
Solvent: c1ccc2c(c1)CCCC2
Product: COc1ccc(-c2cc(=O)n(C)c(=O)[nH]2)cc1OC
Temperature: 170 °C
Yield: 40.3 %

Procedure:
To a solution of ethyl veratroylacetate (8.0 g) in tetralin (24 ml) was added N-methylurea (3.52 g) and the mixture was heated for an hour at 170° C. After being cooled to 95° C., ethyl acetate (33 ml) was added thereto. The precipitate was collected by filtration and washed with ethyl acetate to give 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (3.35 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([OH:28])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1([C:41]([N:43]2[CH:47]=[CH:46]N=[CH:44]2)=[O:42])C=CN=C1.C(N(C(C)C)C(C)C)C.Cl.[F:58][C:59]1[CH:67]=CC=[C:64]2[C:60]=1CN[CH2:63]2>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:41]([N:43]3[CH2:44][C:67]4[C:46](=[CH:63][CH:64]=[CH:60][C:59]=4[F:58])[CH2:47]3)=[O:42])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCOCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Reactant: Fc1cccc2c1CNC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCOCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCOCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4cccc(F)c4C3)C[C@H]1C(=O)N2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCOCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4cccc(F)c4C3)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-hydroxy-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecine-14a-carboxylate (0.096 g, 0.19 mmol) in toluene (5 mL) was added di(1H-imidazol-1-yl)methanone (0.041 g, 0.25 mmol) in one portion. The reaction was stirred at rt for 3 hrs. To the reaction was then added the N-ethyl-N-isopropylpropan-2-amine (0.17 ml, 0.99 mmol), followed by 4-Fluoroisoindoline hydrochloride (0.11 g, 0.38 mmol). The reaction was stirred at 60° C. for 3 hrs. The solvent was removed. The residue was partitioned between ethyl acetate (20 mL) and saturated sodium bicarbonate solution. The organic layer was separated and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Hexane:Ethyl acetate=1:3) to give (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecine-14a-carboxylate as white solid (0.096 g, 75%). MS: Calcd.: 658; Found: [M+H]+ 659.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].S([O-])(O)(=O)=[O:13].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].[OH2:24]>>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([OH:13])=[O:24]
Reactant: O=S(=O)([O-])O
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Br
Yield: 53 %

Procedure:
75 g (0.35 mol) of 2-bromo-4-nitrotoluene, 12 ml of aliquot 336 and 39 g (0.47 mol) of sodium hydrogen sulfate in 1.5 l of water were heated to 80° C. The mixture was stirred well and 183 g (1.16 mol) of potassium permanganate were then added a little at a time. The mixture was then heated under reflux for 45 min. The mixture was filtered through CELITE and the filtrate was concentrated to about 700 ml under reduced pressure. The aqueous solution was acidified with concentrated hydrochloric acid, whereupon the product precipitated. 45 g (53%) of the product were obtained.
Reaction SMILES: [CH3:1]OC(OC)N(C)C.[CH:9]([N:22]1[CH2:25][C:24]([NH:29][CH3:30])([C:26]([NH2:28])=[O:27])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH:9]([N:22]1[CH2:25][C:24]2([C:26](=[O:27])[N:28]=[CH:30][N:29]2[CH3:1])[CH2:23]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(OC)N(C)C
Reactant: CNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Product: CN1C=NC(=O)C12CN(C(c1ccccc1)c1ccccc1)C2
Reaction time: 3 h
Yield: 95.7 %

Procedure:
N,N-Dimethylformamide dimethyl acetal (1.1 ml, 8.3 mmol) was combined with 1-benzhydryl-3-methylaminoazetidine-3-carboxylic acid amide (I-3A-2b; 153 mg, 0.52 mmol) and heated to reflux. After 3 hours, the suspension was cooled and extracted from saturated aqueous NaHCO3 with ethyl acetate. The combined extracts were dried (Na2SO4), and concentrated, in vacuo, to afford I-3A-4a as a solid (152 mg, 96%): +ESI MS (M+1) 306.3; 1H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), 7.47 (d, J=7.5 Hz, 4H), 7.27 (t, J=7.5 Hz, 4H), 7.17 (t, J=7.5 Hz, 2H), 4.57 (s, 1H), 3.58 (s, 3H), 3.55 (d, J=10.0 Hz, 2H), 3.34 (d, J=10.0 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([I:11])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:14]=1[C:15](Cl)=[O:16].Cl>N1C=CC=CC=1>[I:11][C:4]1[S:3][C:2]([NH:1][C:15](=[O:16])[C:14]2[C:13]([Cl:12])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:22])=[N:6][C:5]=1[C:7]([F:10])([F:8])[F:9]
Reactant: Nc1nc(C(F)(F)F)c(I)s1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1nc(C(F)(F)F)c(I)s1)c1c(Cl)cccc1Cl
Temperature: 0 °C
Yield: 70.8 %

Procedure:
2-Amino-5-iodo-4-trifluoromethylthiazole (0.8 g) was dissolved in pyridine (3 ml) and 2,6-dichlorobenzoylchloride (0.6 g) was added at room temperature with stirring. The mixture was stirred for 1 day at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The solid thus obtained was recrystallized from methanol to give N-(5-iodo-4-trifluoromethylthiazol-2-yl)-2,6-dichlorobenzamide (0.9 g), m. p. 157-159° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH:10]([C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:11].Cl[CH2:20][Li].BrCCl.C([Li])CCC>CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:10]([C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:17]=2)[CH3:11])[CH2:20][O:18]1
Reactant: CC(C(=O)c1ccc(F)cc1F)c1ncccn1
Reactant: [Li]CCl
Agent: ClCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(c1ncccn1)C1(c2ccc(F)cc2F)CO1

Procedure:
Treatment of the product of part (ii) (3.10 g) with chloromethyllithium (prepared from bromochloromethane (1.78 g) and a 1.6M solution of n-butyllithium in hexane (8.20 ml)) according to the method of Example 11(iii) gave the title compound as a gum (2.25 g), which was used directly in the next stage.
Reaction SMILES: [NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]=[CH2:10])[CH2:7][S:8][C@H:3]12.C[Si](C)(C)NC(=O)C.[NH2:24][C:25]1[S:26][C:27]([Cl:39])=[C:28](/[C:30](=[N:34]/[O:35]C(=O)C)/[C:31](Cl)=[O:32])[N:29]=1.CO>ClCCl>[NH2:24][C:25]1[S:26][C:27]([Cl:39])=[C:28](/[C:30](=[N:34]/[OH:35])/[C:31]([NH:1][C@@H:2]2[C:14](=[O:15])[N:4]3[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]=[CH2:10])[CH2:7][S:8][C@H:3]23)=[O:32])[N:29]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(=O)O/N=C(\C(=O)Cl)c1nc(N)sc1Cl
Agent: CC(=O)N[Si](C)(C)C
Solvent: CO
Solvent: ClCCl
Product: C=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3nc(N)sc3Cl)[C@H]2SC1
Reaction time: 1 h
Yield: 7.2 %

Procedure:
To a solution of 7β-amino-3-vinyl-3-cephem-4-carboxylic acid (1 g) and N-(trimethylsilyl)acetamide (5.8 g) in dichloromethane (10 ml) was added 2-(2-amino-5-chlorothiazol-4-yl)-2-(Z)-(acetoxyimino) acetyl chloride (1.69 g) under ice-cooling. After being stirred at the same temperature for 1 hour, to this mixture was added methanol (10 ml). After evaporating in vacuo to remove the dichloromethane, the residue was added conc. hydrochloric acid (1.95 ml) at room temperature. After being stirred at the same temperature for 4 hours, the mixture was poured into water (10 ml). The mixture was adjusted to pH 3.5 with 28% ammonium hydroxide in water, and the resulting precipitate was collected by filtration to afford 7β-[2-(2-amino-5-chlorothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (137 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cc1

Procedure:
32.6 g of 4-bromophenol, 34.2 g of benzyl bromide and 42 g of potassium carbonate in 150 ml of dimethylformamide are stirred at 40° C. for 2 hours.
Reaction SMILES: [CH3:1][CH2:2]/[C:3](=[C:11](/[CH2:19][CH3:20])\[C:12]1[CH:18]=[CH:17][C:15]([OH:16])=[CH:14][CH:13]=1)/[C:4]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1.O.[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[OH:16][C:15]1[CH:14]=[CH:13][C:12]([C:11](=[C:3]([C:4]2[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=2)[CH2:2][CH3:1])[CH2:19][CH3:20])=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]
Reactant: O=[N+]([O-])O
Reactant: CC/C(=C(/CC)c1ccc(O)cc1)c1ccc(O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCC(=C(CC)c1ccc(O)c([N+](=O)[O-])c1)c1ccc(O)cc1
Temperature: 5 °C
Reaction time: 5 h
Yield: 18.8 %

Procedure:
Under a nitrogen atmosphere, a suspension of diethylstilbestrol (1.0 g) in acetic acid (160 ml)-water (16 ml) was cooled to 5° C., and 70% nitric acid (0.34 g) was added dropwise thereto. Then, the resulting mixture was heated to 20° C. and stirred for 5 hours. The solvent was distilled off under reduced pressure and an aqueous sodium hydrogencarbonate solution was added to the residue, followed by two runs of extraction with ethyl acetate (150 ml). The combined organic layer was washed with water (200 ml), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (n-hexane:ethyl acetate=9:1) to obtain 3-(4-hydroxy-3-nitrophenyl)-4-(4-hydroxyphenyl)-3-hexene (0.22 g, yield 19%).
Reaction SMILES: C(O[C:6]([N:8](C)[C:9]([CH3:59])([C:11]([NH:13][C@H:14]([C:18]([N:20]([C@@H:22]([C@@H:55]([CH3:58])[CH2:56][CH3:57])[C@H:23]([O:53][CH3:54])[CH2:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C@H:32]([O:51][CH3:52])[C@@H:33]([CH3:50])[C:34](=[O:49])[NH:35][C@H:36]([C:44]1[S:45][CH:46]=[CH:47][N:48]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:26])[CH3:21])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:10])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:6][NH:8][C:9]([CH3:59])([C:11]([NH:13][C@H:14]([C:18]([N:20]([C@@H:22]([C@@H:55]([CH3:58])[CH2:56][CH3:57])[C@H:23]([O:53][CH3:54])[CH2:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C@H:32]([O:51][CH3:52])[C@@H:33]([CH3:50])[C:34](=[O:49])[NH:35][C@H:36]([C:44]1[S:45][CH:46]=[CH:47][N:48]=1)[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:26])[CH3:21])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:10]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC)C(C)C
Reaction time: 8 h

Procedure:
To a mixture of #87 (58 mg, 0.068 mmol, 1 eq.) in dichloromethane (8 mL) was added trifluoroacetic acid (2 mL). After stirring overnight, the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (10 mL), washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated in vacuo to give #88 (52 mg, quantitative). LC-MS 757.6 [M+H+], retention time=0.69 minute; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.64 (br d, J=8.6 Hz) and 8.87 (br d, J=8.6 Hz), total 1H], 7.80-7.85 (m, 1H), [7.77 (d, J=3.3 Hz) and 7.80 (d, J=3.1 Hz), total 1H], [7.63 (d, J=3.1 Hz) and 7.66 (d, J=3.3 Hz), total 1H], 7.20-7.31 (m, 4H), 7.13-7.19 (m, 1H), [5.39 (ddd, J=11, 8.5, 4 Hz) and 5.49-5.56 (m), total 1H], [4.51 (dd, J=9, 8 Hz) and 4.61 (dd, J=9, 8 Hz), total 1H], 3.16, 3.20, 3.21 and 3.25 (4 s, total 6H), 2.94 and 3.03 (2 br s, total 3H), 2.10 and 2.10 (2 s, total 3H), 1.16 (br s, 3H), 1.04-1.12 (m, 6H), 0.72-0.80 (m, 3H).