Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH3:2].[C:18]1([CH2:24][C:25]#[N:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO.[OH-].[Na+]>O>[CH2:1]([CH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[C:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:25]#[N:26])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCCCC(CC)COc1ccc(C=O)cc1
Reactant: N#CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCC(CC)COc1ccc(C=C(C#N)c2ccccc2)cc1

Procedure:
70.2 Grams of 4-[(2-ethylhexyl)oxy]benzaldehyde (prepared as described in the preceding paragraph) and 38.6 g of phenylacetonitrile were added to 800 ml of methanol and stirred cold (10°-15° C.). To this was added (dropwise) 125 ml of aqueous sodium hydroxide (50 percent) with continued stirring at 10°-15° C. for an additional two hours. The mixture was then stirred overnight at room temperature and then poured into cold water and extracted with ethyl acetate. The extract was dried and evaporated to yield α-[[4-(2-ethylhexyloxy)phenyl]methylene]benzeneacetonitrile which was catalytically reduced as follows.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([N+:19]([O-])=O)=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1.C(O)(=O)C>[Zn].O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1
Reactant: COCCOc1cc(Oc2cccnc2)cnc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COCCOc1cc(Oc2cccnc2)cnc1N
Temperature: 105 °C
Yield: 93 %

Procedure:
3-(2-Methoxy-ethoxy)-2-nitro-5-(pyridine-3-yloxy)-pyridine (0.52 mmol) is dissolved in acetic acid (50 eq.). After addition of water (1.5 ml), zinc powder (6.3 eq.) is added and the reaction suspension is heated to 105° C. for 90 minutes. The reaction suspension is cooled to room temperature and filtrated. The filtrate is pored into 3.5% NaOH (30 ml) and extracted with dichloromethane. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-(2-Methoxy-ethoxy)-5-(pyridine-3-yloxy)-pyridine-2-ylamine is obtained as yellow oil in a yield of 93%. HPLC (method C): 0.44 min, LC-MS (method A): 0.46 min, 262.15 (MH+),
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9](=[N:12][OH:13])[C:8]2[N:14]([CH3:17])[CH:15]=[CH:16][C:7]=2[S:6]1(=[O:19])=[O:18].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:11][CH2:10][C:9](=[N:12][OH:13])[C:8]4[N:14]([CH3:17])[CH:15]=[CH:16][C:7]=4[S:6]3(=[O:19])=[O:18])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cn1ccc2c1C(=NO)CCN(CCCCl)S2(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc2c1C(=NO)CCN(CCCN1CCN(c3ccc(F)cc3)CC1)S2(=O)=O
Yield: 29.5 %

Procedure:
A suspension of 112 mg (0.4 mmol) of Compound 20, 108 mg (0.6 mmol) of 1-(4-fluorophenyl)piperazine, 83 mg (0.6 mmol) of potassium carbonate and 120 mg (0.8 mmol) of sodium iodide in 6 ml of acetonitrile was refluxed for 18 hours. The reaction mixture was concentrated under reduced pressure, and a half-saturated aqueous solution of potassium carbonate was added to the residue. The water layer was saturated with sodium chloride, and the thus-obtained mixture was extracted with THF. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: methanol/chloroform=3/97), whereby 53 mg of the title compound were obtained (yield: 29%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[CH2:36][CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:34][C:27]1[CH:28]=[C:29]([O:33][CH2:36][CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:30]=[C:31]([CH3:32])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC6CCOCC6)cc5C)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-29) (138 mg) and 4-(bromomethyl)tetrahydro-2H-pyran (160.3 mg) were suspended in dimethylformamide (5 mL) and potassium carbonate (185.7 mg) was added. The reaction mixture was shaken for 48 h at 60° C. and than directly chromatographed by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 117 mg; LC (method 23): tR=2.26 min; Mass spectrum (ESI+): m/z=561 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(C(C)C)CC)(C)C.[CH3:28][Si:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][O:32][CH2:33]Cl.O>ClCCl>[Cl:1][C:2]1[C:3]([N:12]([CH2:33][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])[S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCCS(=O)(=O)Nc1nc2ccccc2nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1Cl
Temperature: 25 °C
Yield: 94.4 %

Procedure:
Compound A1 (1.22 g, 4.28 mmol) obtained in Reference Example 1 was dissolved in dichloromethane (12.0 mL). Diisopropylethylamine (1.5 mL, 8.6 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.10 mL, 6.40 mmol) were added and the mixture was stirred at room temperature for minutes. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give Compound A5 (1.68 g, 94% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[N:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:12]([C:7]2[CH:6]=[N:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[N:8]=2)=[O:14])[CH2:31][CH2:30]1
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1cnc2cc(F)ccc2n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H](NC(=O)c2cnc3cc(F)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6-fluoroquinoxaline-2-carboxylic acid (35 mg, 0.18 mmol) in dimethylformamide (4 mL) was treated with 1,1′-carbonyldiimidazole (29 mg, 0.18 mmol) and the reaction stirred for 16 hours at ambient temperature. After this time the reaction mixture was treated with trans-4-methylcyclohexylamine hydrochloride (27 mg, 0.18 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.29 mmol) and the reaction stirred 2 hours at ambient temperature. The solvent was evaporated to a solid (700 mg). The solid was dissolved in chloroform (10 mL) and added to diethyl ether (30 mL) The organic solution was washed with water (1×25 mL) and brine. The remaining organic solution was dried over anhydrous MgSO4, filtered, and concentrated to a solid (35 mg) HPLC (10 micron silica, 250×20 mm i.d.) of this material using a gradient of chloroform to 10% ethanol (in chloroform) afforded 20 mg (39%) of 434:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[OH:12].C(Cl)Cl.[CH2:16]([Mg]Br)[C:17]([CH3:20])([CH3:19])[CH3:18]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:16]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[OH:12])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: OC1CCOc2ccc(I)cc21
Reactant: CC(C)(C)C[Mg]Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ccc2c(c1)C(O)CCO2
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of 6-iodochroman-4-ol (1.0 g, 3.6 mmol) in 18 ml of THF, at 0° C., was added the Pd(dppf)Cl2.CH2Cl2 (0.15 g, 0.18 mmol), followed by neopentylmagnesium bromide (10.8 ml, 10.8 mmol, 1.0 M in Et2O). The cold bath was maintained for 10 min., then removed and stirring continued overnight. The mixture was quenched with NH4Cl (30 ml) and extracted with EtOAc (3×50 ml). The combined organic layers were dried over MgSO4 and concentrated in vacuo to yield a brown oil. The crude oil was absorbed onto silica gel followed by flash chromatography (biotage 40S) 10% EtOAc/heptanes to yield 0.36 g (46%) of 6-neopentylchroman-4-ol as a white solid. Rf=0.11. HRMS (ESI+) calcd for C14H20O2 m/z 220.1463 (M+H)+; found 220.1460.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1
Reactant: CCOC(=O)c1cn(C)nc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(C(=O)O)c(Cl)n1

Procedure:
A mixture of 23.9 g (127 mmol) of ethyl 3-chloro-1-methylpyrazole-4-carboxylate and 10.4 g (260 mmol) of sodium hydroxide in 130 mL of water was prepared and was heated at reflux for 3 hr. The solution that formed was cooled to about 0° C. and neutralized to pH 6.5 with concentrated hydrochloric acid with stirring and the precipitate that formed was recovered by filtration, washed with water, and dried under reduced pressure to obtain 18.1 g (89 percent of theory) of the title compound as a white solid melting at 211°-213° C. (d).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:14])=[C:4]([C:11]([OH:13])=O)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[N:32][CH:33]=1>C(#N)C>[CH3:9][N:6]1[C:7]([CH3:8])=[C:2]([F:1])[C:3]([OH:14])=[C:4]([C:11]([NH:27][C:28]2[CH:33]=[N:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)=[O:13])[C:5]1=[O:10]
Reactant: Cc1c(F)c(O)c(C(=O)O)c(=O)n1C
Reactant: N#Cc1ccc(N)cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1c(F)c(O)c(C(=O)Nc2ccc(C#N)nc2)c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
500 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid was dissolved in 5 ml of acetonitrile, and 403 mg of carbonyldiimidazole was added thereto. The mixture was stirred for 1 hour under heat refluxing condition, 297 mg of 5-amino-2-cyanopyridine was added, and the mixture was further stirred for 1 hour under heat refluxing condition. The reaction mixture was cooled to room temperature, and the resulting crystals were collected by filtration to obtain 460 mg of 1,6-dimethyl-5-fluoro-4-hydroxy-2-oxo-N-(6-cyano-3-pyridyl)-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 12) represented by the formula:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.C(OC([NH:15][C:16]1[S:20][CH:19]=[N:18][C:17]=1[C:21](O)=[O:22])=O)(C)(C)C>>[NH2:15][C:16]1[S:20][CH:19]=[N:18][C:17]=1[C:21]([NH:7][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)Nc1scnc1C(=O)O
Reactant: Cn1cc(N)cn1
Product: Cn1cc(NC(=O)c2ncsc2N)cn1
Yield: 32 %

Procedure:
Following the procedures shown in FIG. 4, 1-methyl-1H-pyrazol-4-amine, 5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid were reacted to give 5-amino-N-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide as a white solid (13 mg, 32%) over two steps. ESIMS m/z=336.1 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH:17]([OH:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(C(=O)c3ccccc3)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(C(O)c3ccccc3)cc21
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution of 6-benzoyl-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.35 g, 1.0 mmol) in methanol (10 mL) was added sodium borohydride (0.114 g, 3.0 mmol) and the reaction mixture was stirred for 1 hour. Water (5 mL) was added and the reaction mixture was concentrated. Water was added and the product was extracted with EtOAc. The combined organic phase was dried (MgSO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-60% EtOAc in 40-60 petroleum ether) gave the title compound (0.26 g, 73%) as an oil. MS: [M+H]+=355.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.O.[OH-].[Na+].Cl[CH:16]([F:18])[F:17]>O1CCOCC1.CCOCC>[F:17][CH:16]([F:18])[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1
Reactant: FC(F)Cl
Reactant: CC(=O)c1ccc(O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(OC(F)F)cc1C
Temperature: 65 °C
Reaction time: 1.25 h
Yield: 80.9 %

Procedure:
To a stirred suspension of 1-(4-hydroxy-2-methyl-phenyl)-ethanone (15 g, 100 mmol) in dioxane (30 mL) is added water (25 mL) followed by the addition of NaOH (20 g, 500 mmol). Reaction is heated to 65° C. and passed gaseous chlorodifluoromethane (30 g, 150 mmol) using a glass tube dipped below the solution level for 75 minutes. Stirred for 30 min longer and left at RT over the weekend. Water (100 mL) and ether (40 mL) are added after transferring to a reparatory funnel. A semi-gelatinous material settled at the bottom of the aqueous layer after some time. The bottom aqueous layer is drained off and extracted with ether (2×40 mL). The combined ether layers are washed with water (5×25 mL), dried over solid K2SO4, evaporated and distilled (0.04 mm Hg, 61-64° C.) to afford 1-(4-difluoromethoxy-2-methyl-phenyl)-ethanone (A4) (16.2 g, 81%). Rf in tlc 0.60 with ether.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][N:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH2:19][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH:16]=[CH:15][N:14]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: COc1cc(C=O)ccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(CNc2ccccc2C(=O)O)ccn1
Temperature: 25 °C

Procedure:
A mixture of anthranilic acid (1.37 g, 1.0 mmol), 2-methoxy-pyridine-4-carbaldehyde (1.37 g, 1.0 mmol), and p-toluenesulfonic acid mohohydrate (0.025 g, 0.13 mmol) in 30 mL of anhydrous toluene was stirred at reflux for 1 h, cooled to RT, and NaBH4 (0.9 g) was added. The mixture was stirred at RT for 30 min, and quenched with MeOH. The volatiles were removed under reduced pressure, and the residue was taken up in water. AcOH was added to bring pH to 4, and the mixture was extracted with EtOAc. The combined organic portions were washed with brine, dried over MgSO4, filtered, and condensed. The residue was purified by flash column chromatography to give the titled compound. MS (ES+): 259.0 (M+H)+. Calc'd for C14H12N2O3-258.10.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[F:14][C:15]([F:24])([F:25])[O:16][C:17]1[CH:18]=[CH:19][C:20]([NH:21][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[OH:4])=[CH:22][CH:23]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccccc1O

Procedure:
This compound was obtained as a white solid starting from acetylsalicyclic acid and 4trifluoromethoxyaniline using the same procedure described in example 5.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].C[O-].[Na+].CO.[CH:17]1([CH:23]=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(OC)(OC)OC>[CH:17]1([CH:23]=[CH:1][C:2]([C:4]2[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=2[OH:11])=[O:3])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: O=CC1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: O=C(C=CC1CCCCC1)c1cc(F)ccc1O
Reaction time: 0.75 h

Procedure:
A mixture of 5-fluoro-2-hydroxyacetophenone on Wang resin (4.0 g, 4.6 mmol) was swelled in trimethyl orthoformate (40 mL) for 10 min. 25% NaOMe in MeOH (2.0 g, 9.2 mmol) was added and the mixture was stirred for 45 min. Cyclohexanecarboxaldehyde (1.5 g, 13.8 mmol) was added and stirring was continued for 40 min. The resin was filtered and washed with alternating MeOH and CH2Cl2 (×5) and dried under high vacuum overnight to give 4.3 g of 3-cyclohexyl-1-(2-hydroxy-5-fluorophenyl)-2-propen-1-one on Wang resin.
Reaction SMILES: [CH:1]([C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=O.[C:37]([NH:40][NH2:41])(=[O:39])[CH3:38].Cl>O1CCCC1.O>[C:37]([NH:40][N:41]=[CH:1][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])(=[O:39])[CH3:38]
Reactant: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: CC(=O)NN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NN=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 87.6 %

Procedure:
In a procedure similar to that described in Example I-3, diphenylmethyl 3-formyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (104 mg) and acetylhydrazine (30 mg) are left to react in a mixture of tetrahydrofuran (8 ml) and water (1.51 ml) in the presence of hydrochloric acid (2 equivalents) at room temperature overnight to give diphenylmethyl 3-(2-acetylhydrazono)methyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (101 mg). m.p. 130-138° C. Yield: 88%. IR: νmaxNujol 3250, 1782, 1715, 1670, 1597, 1535 cm-1. UV: λmaxEtOH 327nm(ε=24000). NMR: δCDCl 3 (60MHz) 220s3H, 3.72ABq(39;18Hz)2H, 3.82s2H, 5.00d(5Hz)1H, 5.87dd (9;5Hz)1H, 6.77-7.58ml5H, 8.05s1H, 9.65s1H. [α]D23 -258° (c= 0.493,CHCl3).
Reaction SMILES: [BH4-].[Na+].[N+:3]([CH2:6][CH:7]([C:14]1([C:28]([O:30]C)=O)[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-])=O.N.CCOC(C)=O>CCO.CO.Cl[Ni]Cl>[O:30]=[C:28]1[C:14]2([CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:16][CH2:15]2)[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][NH:3]1
Reactant: COC(=O)C1(C(C[N+](=O)[O-])c2ccccc2)CCCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Ni]Cl
Agent: N
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC2(CC1)C(=O)NCC2c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaBH4 (570 mg, 15.03 mmol) in EtOH (15 ml) under nitrogen was stirred for 20 minutes and added portionwise (4 aliquots) to a cooled (ice-bath) mixture comprising 1-tert-butyl 4-methyl 4-(2-nitro-1-phenylethyl)azepane-1,4-dicarboxylate (step 2) (1.079 g, 2.504 mmol) and NiCl2 (595 mg, 2.504 mmol) in MeOH (25 ml). After stirring at RT for 1 hour, sat. ammonia solution was added (50 ml) followed by EtOAc (60 ml). The mixture was reduced in vacuo and the resulting slurry was partitioned between sat. ammonia solution and EtOAc. The organic portion was separated and the aqueous was further extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with 1-10% MeOH in TBME afforded the title compound;
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])=[O:40]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CS(=O)(=O)CCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCCS(C)(=O)=O)cc1)n2C)c1ccccn1
Yield: 72 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide-hydrochloride and 2-(methylsulphonyl)-ethyl chloroformate. Yield: 72% of theory, C30H33N7O7S (635.7) Rf value: 0.23 (silica gel; dichloromethane/ethanol=19:1) ##EQU84##
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.IC1C=CC=C([N+]([O-])=O)C=1>>[N+:33]([C:29]1[CH:28]=[C:27]([C:24]2[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:26][CH:25]=2)[CH:32]=[CH:31][CH:30]=1)([O-:35])=[O:34]
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2cccc([N+](=O)[O-])c2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: O=[N+]([O-])c1cccc(I)c1
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2cccc([N+](=O)[O-])c2)o1
Yield: 90 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-(3-nitrophenyl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (191 mg, 0.288 mmol) and 1-iodo-3-nitrobenzene following General Procedure A. Flash chromatography (5-10% EtOAc/hexanes) yielded the title compound as a yellow oil (128 mg, 90%): 1H NMR (CDCl3, 500 MHz) δ 8.57-8.56 (m, 1H), 8.26-8.24 (m, 1H), 8.03-8.02 (m, 1H), 7.69 (t, 1H, J=16 Hz), 7.51 (s, 1H), 7.36-7.33 (m, 2H), 7.26-7.23 (m, 3H), 4.94 (t, 1H, J=6.0 Hz), 2.67 (t, 2H, J=7.5 Hz), 2.05-1.96 (m, 2H), 1.72-1.66 (m, 2H), 1.57-1.44 (m, 6H), 0.99 (s, 9H), 0.19 (s, 3H), 0.09 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 166.4, 149.3, 149.2, 143.2, 130.5, 130.1, 130.0, 128.8, 128.6, 126.0, 124.2, 123.2, 119.4, 69.1, 36.8, 36.3, 31.8, 29.6, 26.1, 26.1, 25.5, 18.6, −4.5, −4.6.