Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[CH2:14][CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:13]1([CH2:14][CH3:15])[C:8]2[NH:9][C:4]3[C:5]([C:7]=2[CH2:10][CH2:11][O:12]1)=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH3:22]
Reactant: CCOC(=O)CC(=O)CC
Reactant: OCCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CC1(CC)OCCc2c1[nH]c1ccccc21
Yield: 67.6 %

Procedure:
A mixture of tryptophol (1.612 g, 10 mmol), ethyl propionylacetate (1.730 g, 12 mmol), and p-toluenesulfonic acid monohydrate (0.20 g) in benzene (70 mL) was heated to reflux for 5 hours. It was quenched with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, evaporated to dryness. Flash chromatography on silica gel provided 1.943 g (68%) of the title compound as a solid. mp<80° C. 1H NMR (300 MHz, CDCl3) δ 9.06 (br, 1H), 7.50 (d, 1H), 7.36 (d, 1H), 7.14 (t, 1H), 7.12 (t, 1H), 4.18 (q, 2H), 4.03 (m, 1H), 3.94 (m, 1H), 2.99 (d, 1H), 2.88 (d, 1H), 2.78 (m, 2H), 2.14 (m, 1H), 2.01 (m, 1H), 1.25 (t, 3H), 0.82 (t, 3H); ESI (+) MS m/e=288 (MH+), ESI (−) MS m/e=286 (MH−).
Reaction SMILES: [CH2:1]([N:5]([CH2:11][CH:12](OC)[O:13]C)[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:2]=[CH:3][CH3:4]>C(O)=O>[CH2:1]([N:5]([CH2:11][CH:12]=[O:13])[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCN(CC(OC)OC)C(=O)OCC
Solvent: O=CO
Product: CC=CCN(CC=O)C(=O)OCC
Temperature: 0 °C

Procedure:
90 g (0.39 mol) of ethyl N-(but-2-enyl)-N-(2,2-dimethoxyethyl)-carbamate are heated under reflux with 200 ml of formic acid for one hour. The mixture is poured onto 500 g of ice and extracted with methylene chloride, the organic phases are washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated and the residue is distilled.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:10]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:5][C:6]=1[C:7](=[S:9])[NH2:8].Br[CH2:31][C:32]([C:34]1[CH:35]=[C:36]([NH:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:37]=[CH:38][CH:39]=1)=O>CO>[NH2:10][C:4]1[S:5][C:6]([C:7]2[S:9][CH:31]=[C:32]([C:34]3[CH:35]=[C:36]([NH:40][C:41](=[O:48])[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH:37]=[CH:38][CH:39]=3)[N:8]=2)=[C:2]([NH2:1])[N:3]=1
Reactant: NC(=S)c1sc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)nc1N
Reactant: O=C(CBr)c1cccc(NC(=O)c2ccccc2)c1
Solvent: CO
Product: Nc1nc(N)c(-c2nc(-c3cccc(NC(=O)c4ccccc4)c3)cs2)s1
Yield: 38.3 %

Procedure:
A solution of 4-amino-2-(trityl-amino)-thiazole-5-carbothioic acid amide (304 mg, 0.73 mmol) and N-(3-Bromoacetyl-phenyl)-benzamide (300 mg, 0.94 mmol) in MeOH (30 ml) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 ml). The EtOAc solution was washed with a saturated aqueous solution of NaHCO3 (3×25 ml). The organic layer was separated, dried over MgSO4, and concentrated. Purification of the residue was achieved by silica gel chromatography (75% EtOAc/DCM) providing N-[3-(2′,4′-diamino-[2,5′]bithiazolyl-4-yl)-phenyl]-benzamide (110 mg, 39% yield). mp 159-163° C. (decomp). 1H NMR (CD3OD): δ 8.33 (s, 1H), 8.00-7.97 (m, 2H), 7.75-7.71 (m, 2H), 7.64-7.52 (m, 3H), 7.43 (t, J=7.74 Hz, 1H), 7.33 (s, 1H). FABMS Calcd for C19H15N5OS2: 394.0796. Found: 394.0802.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([F:22])[CH:14]=2)[CH2:8][CH2:7]1)C.O[Li].O>>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([CH:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:24])=[O:3])[CH2:7][CH2:8]2)=[O:23])=[CH:14][C:15]=1[F:22])[CH3:21]
Reactant: CCOC(=O)CN1CCC(C(=O)c2ccc(OCC)c(F)c2)CC1
Agent: [Li]O
Solvent: O
Product: CCOc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
To a solution of [4-(4-ethoxy-3-fluoro-benzoyl)-piperidin-1-yl]-acetic acid ethyl ester (0.19 g, 0.56 mmol in 6 mL of THF and 2 mL of methanol) was added LiOH.H2O (0.12 g, 2.8 mmol in 3 mL of water) and the reaction mixture was stirred at ambient temperature for 1.5 hours. The solvent was removed in vacuo then diluted with 20 mL of water (pH 14). The residue was treated with 12 mL of 1 N HCl (pH 4), frozen at −78° C. and lyophilized for 24 hours to yield the title compound (0.17 g, 0.55 mmol,). MS (ESI) m/z 310.4 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.86 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7](Cl)(=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[C:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: C1CNCCN1
Solvent: ClC(Cl)Cl
Product: O=C(C=Cc1ccccc1)N1CCNCC1
Reaction time: 2 h
Yield: 30 %

Procedure:
Absolute piperazine (206 g) was dissolved in 500 ml of chloroform and 66.3 g of cinnamoyl chloride was added gradually at 0° C while mixing. The addition required 3 hours. After mixing was continued for another 2 hr., precipitates were filtered and then the filtrate (chloroform layer) was washed with 50 ml of 5% sodium hydroxide and 50 ml of water. The residues obtained after solvents were distilled away in vacuo were subjected to silica gel column chromatography (eluants were mixtures of chloroform and methanol). Thus crystalline N-cinnamoyl piperazine was obtained. Melting point of the product was 30°-40° C and the product was very hygroscopic. The yield was 30%.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:18]([C:26]#[N:27])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>C(O)=O>[C:20]1([CH2:19][CH:18]([C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9]3)=[CH:14][CH:13]=2)[C:26]#[N:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(C#N)Cc3ccccc3)cc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: N#CC(Cc1ccccc1)c1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
0.171 mmol tert-butyl-7-(1-cyano-2-phenylethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate were dissolved in 1.3 ml formic acid and stirred at room temperature for 1 h. After addition of saturated NaHCO3 solution the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4 and filtered. Evaporation of the solvent gave 38.5 mg of solid material (86%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH3:17])[CH2:8][CH2:9][NH:10]C(=O)C(F)(F)F)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:10][CH2:9][CH2:8][N:7]([CH3:17])[C:6](=[O:18])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCNC(=O)C(F)(F)F)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(CCN)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 70 %

Procedure:
To a solution of tert-butyl(methyl)[2-[(2,2,2-trifluoroacetyl)amino]ethyl]carbamate (1 g) in methanol (10 ml) in an ice bath was added aqueous 10% potassium carbonate (5 ml). After addition, the reaction mixture was warmed to room temperature and stirring was continued for additional 20 hr. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The insoluble material was removed by filtration and the filtrate was concentrated to obtain the titled compound (451 mg).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O)=[CH:4][CH:3]=1.[O:15]=[C:16]([CH:18]=[C:19]([CH3:21])[CH3:20])[CH3:17].B(F)(F)F.CCOCC.Cl>CCOCC.C([O-])(O)=O.[Na+].CO>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:19]([CH3:21])([CH3:20])[CH2:18][C:16](=[O:15])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)C=C(C)C
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1C(c2ccc(F)cc2)=CC(=O)CC1(C)C
Yield: 37190.6 %

Procedure:
A solution of methyl 4-fluorobenzoylacetate (20.03 g, 97 mmoles), mesityl oxide (14.58 g, 0.145 mmoles) and borontrifluoride etherate (13.77 g, 97 mmoles) was kept at 0° C. for 3 days and diluted with ether and saturated NaHCO3. The organic layer was washed with brine and dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was diluted with 200 ml anhydrous methanol and 20 ml of Triton-B. The mixture was heated at reflux 2 hours, cooled, acidified with aqueous HCl and extracted with ether. The organic layers were washed with aqueous HCl, water and brine and dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was purified by HPLC using 8% ethyl acetate in hexanes as the eluent. Concentration in vacuo of the product-rich fractions provided 14.9 g of the oily product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][CH2:20][O:21][CH3:22].C(OCC)(=O)C>CN(C=O)C>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:19][CH2:20][O:21][CH3:22]
Reactant: COCCCl
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cc(C=O)ccc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of 3-hydroxy-4-methoxybenzaldehyde (8.0 g) in DMF (60 mL) was added K2CO3 (8.0 g) and 1-chloro-2-methoxyethane (5.1 g). The resulting mixture was stirred at 80° C. overnight. After reaction finished, ethyl acetate (200 ml) was added, and washed with 2 N aqueous HCl solution, brine, dried over Na2SO4, filtered, concentrated. The residue was washed with petrol ether to give 4-methoxy-3-(2-methoxyethoxy)benzaldehyde (11 g) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ: 9.84 (s, 1H); 7.49-7.43 (m, 2H); 6.98 (d, J=8.0, 1 H); 4.25-4.22 (m, 2H); 3.95 (s, 3H); 3.83-3.81 (m, 2H); 3.46 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=2)[N:5]=[C:4]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:3]=1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[N:31]1([C:2]2[N:7]=[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][CH:9]3[C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH:14]=3)[N:5]=[C:4]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[CH:3]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1
Reactant: Cc1cc(Nc2cc(Cl)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Reactant: C1CNCCN1
Product: Cc1cc(Nc2cc(N3CCNCC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1

Procedure:
Starting materials: 6-chloro-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 17) and piperazine. Yield: 204 mg, 73% as a white powder.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>>[CH2:10]([NH:13][CH2:1][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[OH:9])[CH:11]=[CH2:12]
Reactant: c1ccc(C2CO2)cc1
Reactant: C=CCN
Product: C=CCNCC(O)c1ccccc1

Procedure:
A mixture of styrene oxide (24 mL, 0.2 moles) and allylamine (60.8 mL, 0.8 moles) was heated to reflux under nitrogen atmosphere, for 24 hours. Upon cooling, product crystallized and was triturated with hexane. Recrystallization from hexane afforded the title compound essentially uncontaminated by the other possible regioisomer. Ms m+/z=177; H1NMR (CDCl3): δ 7.3 (br.s, 5H), 5.6-6.1 (m, 1H), 4.9-5.4 (m, 2H), 4.75 (m, 1H), 3.2 (br.d, 2H), 2.9 (br.s, 2H), 2.7 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)[CH3:2].[CH2:27]([N:29]1[CH:34]=[C:33]([CH:35]=O)[C:32](=[O:37])[NH:31][C:30]1=[O:38])[CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.O>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([N:19]4[CH2:20][CH2:21][N:22]([CH2:35][C:33]5[C:32](=[O:37])[NH:31][C:30](=[O:38])[N:29]([CH2:27][CH3:28])[CH:34]=5)[CH2:23][CH2:24]4)[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)[CH3:26]
Reactant: CCn1cc(C=O)c(=O)[nH]c1=O
Reactant: CCN(CC)c1ccc(-c2nc3c(N4CCNCC4)cccc3[nH]2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCN(CC)c1ccc(-c2nc3c(N4CCN(Cc5cn(CC)c(=O)[nH]c5=O)CC4)cccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a solution of Diethyl-[4-(4-piperazin-1-yl-1H-benzoimidazol-2-yl)-phenyl]-amine (1.0 g, 2.0 mMol) in N-methylpyrrolidinone (10 mL) was added 1-Ethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbaldehyde (0.404 g, 2.40 mMol) followed by sodium triacetoxyborohydride (0.849 g, 4.01 mMol) and the mixture stirred at room temperature overnight. Upon arrival the crude reaction mixture was diluted with water (2 mL), filtered, and purified by RP-HPLC (Method E) to yield 168 mg (17% yield) of 5-{4-[2-(4-Diethylamino-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-ylmethyl}-1-ethyl-1H-pyrimidine-2,4-dione as a very light yellow solid. 1H NMR (DMSO-d6): δ=12.33 (s,1H), 11.25 (s,1H), 7.91 (d, 2H, J=9 Hz), 7.66 (s, 1H), 6.96 (m, 2H), 6.77 (d,2H, J=9 Hz), 6.45 (dd, 1H, J=6.0, 2.8 Hz), 3.74 (q, 2H, J=7.1 Hz), 3.53 (br s, 4 h), 3.40 (q, 4H, J=7.1 Hz), 3.23 (s, 2H), 2.62 (m, 4H), 1.18 (t, 3H, J=7.1 Hz), 1.13 (t, 6H, J=7.1 Hz). LC/MS (Method A), rt=0.85 mins., purity=99.2%, calculated mass=501, [M+H]+=502, [M−H]=500. HPLC (Method D): rt=5.5 mins., purity=99.3% @ 210-370 nm and 98.6% @ 372 nm.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:20]=CC1C=CC=CC=1)([CH2:8][CH2:9][CH2:10][CH2:11][N:12]=CC1C=CC=CC=1)[C:4]([O:6][CH3:7])=[O:5].[ClH:28]>CCOCC>[ClH:1].[ClH:28].[Cl:1][CH2:2][C:3]([NH2:20])([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CCl)(CCCCN=Cc1ccccc1)N=Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: COC(=O)C(N)(CCl)CCCCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-chloromethyl-2,6-bis(benzylideneamino)hexanoate (2.85 g, 7.4 mmol) in ether (6 ml), is added 1N HCl (20 ml) under vigorous stirring. The reaction mixture is stirred overnight at room temperature and then extracted with ether. The aqueous phase is evaporated to dryness under vacuo to afford methyl 2-chloromethyl-2,6-diaminohexanoate dihydrochloride as an oily and hygroscopic residue (2.05 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:32][C:8]([CH2:9][C:10]2[CH2:11][S:12][C@@H:13]3[C@H:20]([NH:21]C(=O)CC4C=CC=CC=4)[C:19](=[O:31])[N:14]3[C:15]=2[C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1)=[O:4].N1C=CC=CC=1.C[Si](C)(C)Cl.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl.C(N(CC)CC)C.C(O)=O.CO>[NH2:21][C@@H:20]1[C:19](=[O:31])[N:14]2[C:15]([C:16]([OH:18])=[O:17])=[C:10]([CH2:9][C:8]3[O:32][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH2:11][S:12][C@H:13]12
Reactant: COC(=O)c1ccc(CC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)o1
Agent: C[Si](C)(C)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=CO
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)o1
Reaction time: 0.67 h

Procedure:
A suspension of 0.456 g of 3-(5-methoxycarbonylfurfuryl)-7β-phenylacetylamino-ceph- 3-em-4-carboxylic acid in 30 ml of absolute methylene chloride is stirred for 30 minutes at 30° with 0.89 ml of absolute pyridine and 1.5 ml of trimethylchlorosilane. The resulting clear yellow solution is treated with 1.08 ml of pyridine and cooled to below -20°, then 8.9 ml of an 8% phosphorous pentachloride solution in methylene chloride is added dropwise and the solution is stirred for 40 minutes at a temperature of -12°. The brown solution is cooled again to below -20° and treated with 12.1 ml of absolute methanol. The mixture is allowed to react for 30 minutes at room temperature, whereupon the solution largely loses its colour. Upon addition of 2.5 ml of 25% aqueous formic acid, the pH of the solution is adjusted to 2.0 with 2.6 ml of triethylamine. The resulting suspension is further stirred for 30 minutes at room temperature. The pH is raised to 3.5 by the further addition of 9.6 ml of triethylamine. The suspension is left to stand for 1 hour at 0°; the fine, rather stimy precipitate is filtered off, washed with methanol, methylene chloride and diethyl ether and dried under a high vacuum. The 7β-amino-3-(5-methoxycarbonyl-furfuryl)-ceph-3-em-4-carboxylic acid is obtained in the form of a yellowish, microcrystalline powder. Additional, somewhat less pure material can be isolated by digesting the evaporated mother liquors and rinsing liquors with methylene chloride; ultraviolet absorption spectrum (in 0.1 N aqueous sodium hydrogen carbonate solution): λmax = 270 mμ (ε = 21400) and λmin = 234 mμ (ε = 8200); infrared absorption spectrum (in mineral oil): characteristic bands at 3,13μ, 3,83μ, 4,24μ, 5,54μ, 5,77μ, 6,17μ, 6,54μ, 6,58μ, (shoulder), 7.08μ, 7,39μ, 7,63μ, 7,72μ, 8,38μ, 8,84μ, 9,49μ, 9,78μ, 10,12μ, 12,62μ and 13,21μ.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]=[C:5]1[C:9](=[O:10])[O:8][C:7]([CH3:11])=[N:6]1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:9](=[O:10])/[C:5](/[NH:6][C:7](=[O:8])[CH3:11])=[CH:4]/[CH2:3][O:2][CH3:1]
Reactant: C[O-]
Reactant: COCC=C1N=C(C)OC1=O
Agent: [Na+]
Solvent: CO
Product: COC/C=C(\NC(C)=O)C(=O)OC

Procedure:
A solution consisting of 19 g (0.165 mol) of oxazolones 3 and 100 ml of methanol was treated with solid sodium methoxide until the reaction mixture was slightly basic (pH 9 as indicated by moist pH paper). The solution was stirred for 3/4 hr. at room temperature. The reaction mixture was concentrated in vacuo, and the residue taken up in 500 ml of ether. Petroleum ether (bp 35°-60°) was added until the solution was slightly turbid. An additional portion of ether was added to clear the turbidity and the resultant solution was treated with charcoal and filtered through Celite®. The solvents were removed in vacuo, and the residue dried at 0.1 mm. Crystallization from ether/petroleum ether (bp 35°-60°) yielded Z-2-acetamido-4-methoxy-2-butenoic acid methyl ester (4): mp 60°-61°; IR (CHCl3) 3415, 1720, 1700, 1500 cm-1 ; UV (EtOH) λmax 226 nm (ε7500); NMR (CDCl3) δ 7.5 (broad, 1H, NH), 6.7 (t, 1H, --CH2CH=), 4.1 (d, 2H, --CH2CH=), 3.8 (s, 3H, CH3O2C--), 3.4 (s, 3H, CH3OCH2 --), 2.14 (s, 3H, CH3CONH--). (Calcd. for C8H13NO4 : C, 51.33; H, 7.00; N, 7.48. Found: C, 51.20; H, 7.13; N, 7.69.)
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:27])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2ccccc2O1
Reaction time: 2 h
Yield: 76.3 %

Procedure:
130 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 10 ml of dichloromethane at room temperature and 93 mg of m-chloroperbenzoic acid were added. After 2 hours thin-layer chromatography indicated that some starting material was still present, whereupon further m-chloroperbenzoic acid was added until the reaction was complete. The mixture was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water, dried over sodium sulphate and evaporated to give 105 mg of 2-(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide in the form of an oil. NMR (300 MHz, CDCl3): 8.36-8.30 (1H, m) 7.21-7.04 (4H, m), 6.89-6.76 (3H, m), 5.36-5.25 (1H, m), 2.46 (1H, dd, 14Hz, 6.5Hz), 1.75 (1H, broad t, 14Hz), 1.44 (3H, s), 1.40 (3H, s). MS (EI): 255 (M+ , 238 (M+ -OH).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH3:26])(=[O:35])=[O:34])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]([SH:11])([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:5])[CH3:4].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:3]([S:11][CH2:12][CH:14]1[O:16][CH2:15]1)([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:5])[CH3:4]
Reactant: ClCC1CO1
Reactant: CC(C)(C)CC(C)(C)S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)CC(C)(C)SCC1CO1

Procedure:
A solution of 66 parts by weight of sodium hydroxide, 300 parts by weight of water and 8 parts by weight of tetrabutylammonium chloride is added dropwise within 70 minutes at 15° to 20° C., with stirring and partial cooling (particularly at the commencement of the addition) to a mixture of 219 parts by weight of tert-octylmercaptan and 135 parts by weight of epichlorohydrin. The reaction mixture is subsequently stirred at 50° C. for 1 hour; the aqueous phase is then separated, and the organic phase is washed with 200 parts by weight of water. The organic phase is finally distilled in vacuo to thus obtain the tert-octylglycidyl thioether as a colourless liquid having a boiling point of 74° to 75° C. at 0.02 mbar, and a refractive index of nD20 =1.4803; the yield is 250 parts by weight, which corresponds to 82% of the theoretical yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C(C1C=CC([F:62])=CC=1)#C>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([F:62])=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: Fc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Yield: 72 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-4-fluorobenzene in 72% yield.