Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:49]1[CH:53]=[N:52][S:51][N:50]=1)[C:19]([NH:21][CH:22]1[C:47](=[O:48])[N:24]2[C:25]([C:31]([O:33]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]12)=[O:20])=[O:14])(C)(C)C.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[C:13]([CH2:15][O:16][N:17]=[C:18]([C:49]1[CH:53]=[N:52][S:51][N:50]=1)[C:19]([NH:21][CH:22]1[C:47](=[O:48])[N:24]2[C:25]([C:31]([OH:33])=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]12)=[O:20])([OH:14])=[O:12]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cnsn3)[C@H]2SC1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3cnsn3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
Trifluoroacetic acid (6.75 ml) was added to a solution of benzhydryl 7-[2-tert-butoxycarbonylmethoxyimino-2-(1,2,5-thiadiazol-3-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.9 g) in methylene chloride (5.8 ml) and anisole (1.9 ml) under ice-cooling, and the mixture was stirred for 4 hours at ambient temperature. The resultant solution was added dropwise to diisopropyl ether (100 ml) and the precipitates were collected by filtration. The precipitates were added to a mixture of water and ethyl acetate and adjusted to pH 7.0 with 10% aqueous sodium hydroxide. The separated aqueous layer was adjusted to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride and then dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether and collected by filtration to give 7-[2-carboxymethoxyimino-2-(1,2,5-thiadiazol-3-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0.96 g).
Reaction SMILES: [Cl:1][C:2]1[C:15]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=3)=[N:17]2)=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[C:4]([F:29])[CH:3]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[C:4]([F:29])=[CH:3][C:2]([Cl:1])=[C:15]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3[CH:23]=[CH:24][C:25]([I:28])=[CH:26][CH:27]=3)=[N:17]2)[CH:14]=1
Reactant: O=C(NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F
Yield: 89.1 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-2-fluoro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)-2,2,2-trifluoroacetamide (0.550 g, 1.01 mmol), KOH (0.285 g, 5.09 mmol), water (5 mL) and THF (15.0 mL) to afford 0.400 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.59 (m, 211), 3.71 (s, 1H), 7.38 (d, J=9.6 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.60-7.69 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:27][CH2:26][CH2:25][C@:9]32[N:13]([CH3:14])[C:12](=[O:15])[N:11]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C:10]3=[O:24])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([N:11]2[C:10](=[O:24])[C@:9]3([CH2:25][CH2:26][CH2:27][C@H:8]3[C:5]3[CH:6]=[CH:7][C:2]([C:32]4[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=4)=[CH:3][CH:4]=3)[N:13]([CH3:14])[C:12]2=[O:15])[CH:21]=[C:20]([Cl:22])[CH:19]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(Br)cc1
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(-c2ccc(F)cc2)cc1
Yield: 14.6 %

Procedure:
Using the procedure described in Example 8 (5R*,6S*)-6-(4-bromophenyl)-3-(3,5-dichlorophenyl)-1-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (80 mg, 0.17 mmol) (Example 1) was reacted with 4-fluorophenylboronic acid (71.4 mg, 0.51 mmol) to yield the above-titled compound (12 mg) as a white solid. 1H NMR (CDCl3) δ 7.45–7.55 (4H, m), 7.05–7.25 (5H, m), 6.62 (2H, m), 3.46 (1H, dd, J1=12.9 Hz, J2=6.3 Hz), 3.18 (3H, s), 2.5–2.75 (1H, m), 1.85–2.45 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1)=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][CH2:6][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][OH:15])=[CH:12][CH:13]=1
Reactant: COC(=O)CCC(=O)c1ccc(CO)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCc1ccc(CO)cc1
Reaction time: 4 h

Procedure:
4-[4-(Hydroxymethyl)-phenyl]-4-oxo-butyric acid methyl ester (8 g, 36 mmol) is dissolved in methanol. Pd/C (0.8 g, 10% wt dry basis) is added. The flask is then sealed with a rubber septum and a balloon filled with H2 gas is applied to it. The heterogeneous mixture is then stirred for 4 hours after which the balloon and the stopper are removed and the hydrogen is allowed to escape. The reaction mixture is then filtered through a pad of diatomaceous earth (Celite®) and the filtrate so obtained is concentrated in vacuo to provide the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]#[N:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.Cl.CCOC(C)=O.P(S)(OCC)(OCC)=[S:22]>CO.C(OC(C)C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12](=[S:22])[NH2:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1
Reactant: CCOP(=S)(S)OCC
Reactant: Cc1nc2ccc(Br)cn2c1C#N
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: Cc1nc2ccc(Br)cn2c1C(N)=S
Temperature: 60 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a suspension of 6-bromo-2-methylimidazo[1,2-a]pyridine-3-carbonitrile (6.2 g, 26.4 mmol) obtained above in MeOH (88 mL), were added 4N solution of hydrogen chloride in EtOAc (22 mL, 88.0 mmol) and O,O-diethyl hydrogen dithiophosphate (25 mL, 158 mol), and the mixture was stirred at 60° C. for 3 h. The mixture was allowed to cool to rt, and diluted with diisopropyl ether (100 mL). The resulting precipitate was collected by filtration and washed with diethyl ether to give the title compound (6.2 g, 77%) as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C@H:4]1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1.C(N(CC)CC)C.C([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C.O>C1COCC1>[Cl:24][C:19]1[CH:18]=[C:17]([C@H:4]2[C@H:3]([CH2:2][NH:1][C:36](=[O:35])[CH2:37][OH:38])[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CN)[C@H](c2ccc(Cl)c(Cl)c2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](CNC(=O)CO)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(aminomethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (170 mg) and triethylamine (0.126 mL) in THF (4.0 ml) was added acetoxyacetyl chloride (93 mg), and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in methanol (4.0 mL) was added potassium carbonate (273 mg), and the mixture was stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure, the residue was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (183 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:15]=1)[C:7](=[O:14])[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:31])[CH2:29][CH3:30]>C(Cl)(Cl)Cl>[CH2:28]([NH:31][C:11]([C:8]1[C:7](=[O:14])[N:6]2[CH:15]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)=[O:13])[CH2:29][CH3:30]
Reactant: Cc1ccc2ncc(C(=O)O)c(=O)n2c1
Reactant: CCCN
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1cnc2ccc(C)cn2c1=O
Reaction time: 0.08 h
Yield: 89.2 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate dissolved in 40 ml of chloroform is dropped to the above mixture at -18° C. during 20 minutes. After stirring for 5 minutes, 5.2 (0.088 mol) of propylamine dissolved in 80 ml of chloroform are dropped to the above solution at -18° C. during 60 minutes. The reaction mixture is stirred at -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to obtain 17.5 g (89.2%) of the named compound as yellow crystals after recrystallization from ethanol, m.p.: 126°-128° C.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3]O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:23]2)=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][SH:23]
Reactant: COc1ccc(C(C)(N)CO)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)(N)CS)cc1
Temperature: 25 °C

Procedure:
A solution of 1 mmol of 2-amino-2-(4-methoxyphenyl)propan-1-ol (Example 3k) and 0.5 mmol of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) [19172-47-5] in 10 ml of toluene is heated to reflux for 2 hours. The reaction mixture is cooled to room temperature and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60 F).
Reaction SMILES: [CH2:1]1[CH:13]2[CH:5]([C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:12]2=O)[CH2:4][CH2:3][CH2:2]1.[CH3:15][Mg]Br.Cl>O1CCCC1>[CH3:15][C:12]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]2[C:13]=1[CH2:1][CH2:2][CH2:3][CH2:4]2
Reactant: O=C1C2=C(CCCC2)C2CCCCC12
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC1=C2CCCCC2C2=C1CCCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To a solution of 1,2,3,4,4a,5,6,7,8,9a-decahydrofluoren-9-one (90.7 mg, 0.477 mmol) in tetrahydrofuran (5 ml), 0.35 ml (1.05 mmol) of methylmagnesium bromide (3.0 M in Et2O) was added dropwise under nitrogen at −78° C. The resulting cloudy mixture was kept at −78° C. for 3 hours and then allowed to warm to room temperature and stirred for 14 hours. The reaction mixture was acidified with 15% aqueous HCl (5 ml), followed by extraction in Et2O (4×20 ml). All organic layers were combined, washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 82.5 mg (92%) of 2,3,4,4a,5,6,7,8-octahydro-9-methyl-1H-fluorene and 1,3,4,5,6,7,8,9a-octahydro-9-methyl-2H-fluorene in the ratio of 3 to 1. 1H-NMR (CDCl3): δ 2.6–0.9 (m), 13C NMR: 155.77, 136.49, 133.51, 111.70, 61.12, 50.29, 42.14, 29.74, 27.41, 25.46, 25.11, 23.38, 22.81.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:34])=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=4)=[N:17]3)[CH2:12][CH2:11]2)=[O:9])[CH:7]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[Cl:34][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:37])[CH3:36])=[CH:7][C:6]=1[C:8]([N:10]1[CH2:11][CH2:12][CH:13]([N:16]2[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)=[N:17]2)[CH2:14][CH2:15]1)=[O:9]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(N)ccc4Cl)CC3)C(=O)C2(C)C)cc1OC
Solvent: ClCCl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(NC(C)=O)ccc4Cl)CC3)C(=O)C2(C)C)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.18 g of 2-{1-[(5-amino-2-chlorophenyl)carbonyl]piperidin-4-yl}-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 91) are dissolved in 5 ml of DCM, 0.17 ml TEA and 0.032 ml acetyl chloride are added, and the reaction mixture is stirred at RT for about 16 h until the reaction is completed according to TLC analysis. The mixture is washed with 0.5 M aqueous sulfuric acid, twice with 1 M aqueous sodium carbonate solution and with brine. The organic phase is dried over MgSO4, and the solvent is removed under reduced pressure resulting in the crude product, which is purified by column chromatography (silica gel and EA) yielding the title compound.
Reaction SMILES: C(OC)(=O)C1C=CC(C(OC)=O)=CC=1.C(O)CCCO.C[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1N=C=O>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:25]1([N:28]=[C:29]=[O:30])[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: COC(=O)c1ccc(C(=O)OC)cc1
Solvent: OCCCCO
Product: O=C=Nc1ccccc1
Temperature: 210 °C
Reaction time: 2 h

Procedure:
In a 1 liter three-necked resin flask equipped with nitrogen inlet and outlet, thermometer, condenser and mechanical stirrer, were placed 194 grams (1 moles) of dimethyl terephthalate, 207 grams (2.3 moles) of 1,4-butanediol and 0.173 grams of titanium tetraisopropoxide. The mixture was heated at 210° C. for 2 hours while distilling out methanol. The resulting mixture was heated at 250° C. for 30 minutes, and then vacuum was applied for 2 hours. After vacuum was released and replaced with nitrogen, 2,4-toluenediisocyanate (16.02 grams, 0.092 moles) was added into the flask. The resulting polymer was stirred for 40 minutes at 250° C., and then was cooled to room temperature to obtain phenyl isocyanate terminated copolyester with an intermediate molecular weight, I.V.1.18 dL/g as determined at 25° C. and 0.1% concentration in HFIP/PFP 50/50; Tmp 220° C.; heat of fusion 38 j/g; Tg 55° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[NH:5][C:6](=[O:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.O>C(O)(=O)C>[Br:1][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:14])[NH:5][C:4]=1[CH3:3]
Reactant: Cc1cc2ccccc2c(=O)[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]c(=O)c2ccccc2c1Br
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A solution of bromine 491 mL, 9.58 mmol) in acetic acid (10 mL) is added to a stirred solution of 3-methyl-2H-isoquinolin-1-one (1.45 g, 9.12 mmol) in acetic acid (1 mL). After 3 hr, water (60 mL) is added and the resulting solids are collected by filtration to afford 4-bromo-3-methyl-2H-isoquinolin-1-one (1.90 g, 88% yield) as a white solid. LC/MS: MS m/e=238/240 (M+H); RT 2.97 min.
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)(C)(C)C.C([Li])CCC.CN(C)C=O.Cl>O1CCCC1>[NH:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[CH:14]=[CH:6]1
Reactant: Cc1cccnc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1cnc2[nH]ccc2c1
Temperature: -15 °C
Reaction time: 1 h
Yield: 134 %

Procedure:
(3-Methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (5 g, 24 mmol) was dissolved in tetrahydrofuran (96 mL) and cooled in an ice-salt bath to −15° C. Butyl lithium solution (1.6 M in hexanes, 30 mL, 48 mmol) was added drop wise over 30 min. After an additional 1 h, N,N-dimethylformamide (1.9 mL, 34.5 mmol) was added and the reaction mixture warmed to 25° C. over 16 h. The reaction mixture was added very slowly to approximately 150 mL of 6M HCl solution. The resulting mixture was warmed to 55° C. for 2 h, then cooled, the phases separated, and ethyl acetate was added to the aqueous layer. 6M sodium hydroxide solution was slowly added until the pH 6, then the layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined ethyl acetate extracts were washed with sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo to give 1H-pyrrolo[2,3-b]pyridine (3.8 g, 134%) as a brown semisolid. This was used directly in the next step without further purification. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 10.86 (br. s., 1H) 8.28 (dd, J=4.9, 1.5 Hz, 1H) 7.98 (dd, J=7.7, 1.7 Hz, 1H) 7.36 (d, J=3.4 Hz, 1H) 7.10 (dd, J=7.9, 4.9 Hz, 1H) 6.51 (d, J=3.4 Hz, 1H); LCMS (EI/CI) m/z: 119 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:4]=2[C:5](=[O:8])[NH:6][N:7]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C.O>[NH2:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=3[CH3:18])[C:4]=2[C:5](=[O:8])[N:6]([CH3:23])[N:7]=1
Reactant: Cc1cc(C)c(-n2ccc3c(N)n[nH]c(=O)c32)c(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(-n2ccc3c(N)nn(C)c(=O)c32)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.6 %

Procedure:
To an ice-cooled solution of 4-amino-1-mesityl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (268 mg, 1.0 mmol) in DMF (3 ml) was added sodium hydride (60% in oil, 44 mg, 1.1 mmol) and the mixture was stirred for 10 minutes. Methyl iodide (0.081 ml, 1.3 mmol) added and the mixture was stirred at room temperature for 1 hour. Additional sodium hydride (60% in oil, 44 mg, 1.1 mmol) and methyl iodide (0.081 ml, 1.3 mmol) were added and the mixture was stirred for 1 hour. The resulting mixture was diluted with water (30 ml) and extracted with ethyl acetate (30 ml×2). The extracts were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to silica gel column chromatography eluting with hexane/ethyl acetate (1:1-2:3) to give 140 mg (50%) of the title compound as crystals.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][S:29][CH2:30][CH:31]=[CH2:32])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][S:29][CH2:30][CH:31]=[CH2:32])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCSCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C=CCSCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 84.8 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(2-allylthioethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), conc. hydrochloric acid (1.19 g.), tetrahydrofuran (7.5 g.) and methanol (22.5 ml.) were treated in a similar manner to that of Example 1-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(2-allylthioethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.) powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1.[Br:25]N1C(=O)CCC1=O>C(#N)C.O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[C:6]=1[Br:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cc(OCc2ccccc2)c2cc(F)ccc2c1
Solvent: CC#N
Solvent: O
Product: COC(=O)Cc1cc(OCc2ccccc2)c2cc(F)ccc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a stirred solution of (4-benzyloxy-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (350 mg, 1.08 mmol) in acetonitrile (10 mL) was added N-bromosuccinimide (385 mg, 2.16 mmol). After being stirred at room temperature for 1 hour, the resulting mixture was diluted with water (20 mL), and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with water (15 mL) and brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 0-20% ethyl acetate in hexanes) to afford (4-benzyloxy-1-bromo-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (400 mg, 92%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:15])[N:5]([CH2:13][CH3:14])[C:6](=[S:12])[N:7]([CH2:10][CH3:11])[C:8]=1[NH2:9].C(=O)([O-])[O-].[Na+].[Na+].[CH:22]1([C:25](Cl)=O)[CH2:24][CH2:23]1>N1C=CC=CC=1.CCOCC>[CH2:13]([N:5]1[C:4](=[O:15])[C:3]2[NH:2][C:25]([CH:22]3[CH2:24][CH2:23]3)=[N:9][C:8]=2[N:7]([CH2:10][CH3:11])[C:6]1=[S:12])[CH3:14]
Reactant: O=C(Cl)C1CC1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCn1c(=O)c2[nH]c(C3CC3)nc2n(CC)c1=S

Procedure:
25.1 g (100 mM) of 5,6-diamino 1,3-diethyl-2-thiouracil HCl were dissolved in 400 ml of pyridine, 12.72 g (120 mM) of sodium carbonate added, and under cooling a solution of 10.77 ml (120 mM) of cyclopropane carbonyl chloride in 50 ml of dried ether added within 10 minutes. After 20 min the solvents were evaporated in vacuo. The residue was treated with 200 ml of water and about 50 ml were removed again in vacuo. The suspension was diluted with 100 ml of 2N aqueous sodium hydroxide (NaOH) and heated under reflux for 30 minutes. A further 80 ml was distilled off during this time. After cooling the solution was Acidified with 5N aqueous hydrochloric acid (HCl) to pH 5.5; 200 ml of water was added and the resulting suspension filtered. The solid was collected and washed, redissolved in 200 ml of 1N NaOH, treated twice with 0.4 g of charcoal, filtered and acidified again to pH 4.5. The solid was collected again, washed and dried to give 25.5 g of a solid which was suspended in 400 ml of hot methanol. The solid was collected again, washed and dried to give 23.5 g (89.0%) of 2-thioxanthine with mp subl. 265-7° C.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH3:9][O:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][O:16][CH2:17][C@H:18]([CH3:34])[C@H:19]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C@@H:20]([CH3:25])[CH2:21][CH2:22][CH2:23][OH:24])=[CH:13][CH:12]=1.N1C=CN=C1>C(Cl)Cl>[Si:27]([O:26][C@H:19]([C@@H:20]([CH3:25])[CH2:21][CH2:22][CH2:23][O:24][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])[C@@H:18]([CH3:34])[CH2:17][O:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:36][CH:35]=1)([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:29])[CH3:28]
Reactant: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TBSCl (0.92 g, 6.11 mmol) was added to a solution of above alcohol 61 (2.51 g, 6.11 mmol) and imidazole (0.46 g, 6.76 mmol) in CH2Cl2 (20 mL). The resulting slurry was stirred for 1 h at room temperature. The organic phase was washed with water (100 mL) and brine (2×100 mL). After drying over MgSO4, filtration and evaporation under vacuum, the residue was used directly in next step: IR (CHCl3) 2930, 2856, 1613, 1513, 1471, 1360, 1250, 1098, 1040, 835, 773 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.29-7.26 (m, 2H), 6.90-6.88 (m, 2H), 4.46 (d, J=11.6 Hz, 1H), 4.42 (d, J=11.6 Hz, 1H), 3.81 (s, 3H), 3.62 (t, J=6.3 Hz, 2H), 3.58-3.52 (m, 2H), 3.28 (dd, J=8.8, 7.7 Hz, 1H), 2.02-1.94 (m, 1H), 1.66-1.54 (m, 2H), 1.52-1.39 (m, 2H), 1.28-1.18 (m, 1H), 0.99 (d, J=6.9 Hz, 3H), 0.94 (s, 9H), 0.92 (s, 9H), 0.89 (d, J=6.8 Hz, 3H), 0.09 (s, 6H), 0.07 (s, 3H), 0.06 (3H); 13C NMR (75 MHz, CDCl3) δ 159.0, 130.9, 129.0, 113.6, 77.5, 72.8, 72.6, 63.4, 55.1, 38.0, 36.3, 31.1, 30.8, 26.1, 25.9, 18.4, 18.3, 15.2, 14.4, −3.8, −4.1, −5.3; LRMS (ESI) 547.4 [M+Na]+413.3, 212.1; HRMS (ESI) calcd for C29H56O4Si2Na 547.3615 [M+Na]+, found 547.3638; [α]20D−9.9 (c 2.5, CHCl3).