Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25](OCC)=[O:26])[C:22]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:34][CH:33]=3)=[N:21]2)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][OH:26])[C:22]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:34][CH:33]=3)=[N:21]2)=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCc1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Lithium aluminium hydride (1.52 g) was added to a solution of ethyl 1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyloxy)-1H-pyrazole-4-carboxylate (11.00 g) in tetrahydrofuran (200 ml) at 0° C., and the mixture was stirred at room temperature for one hour. After water was added to the reaction mixture, the precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The crystals obtained were collected by filtration to yield [1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyloxy)-1H-pyrazol-4-yl]methanol (7.11 g, yield: 70%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 128–129° C.
Reaction SMILES: C(OP([CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])(OCC)=O)C.[H-].[Na+].[Cl:30][C:31]([F:35])([F:34])[CH:32]=O.[OH-].[Na+]>C1COCC1.O>[Cl:30][C:31]([F:35])([F:34])/[CH:32]=[CH:9]/[C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)=[O:11].[Cl:30][C:31]([F:35])([F:34])/[CH:32]=[CH:9]\[C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)=[O:11]
Reactant: O=CC(F)(F)Cl
Reactant: CCOP(=O)(CC(=O)N1CCN(c2ccnc3ccccc23)CC1)OCC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(/C=C/C(F)(F)Cl)N1CCN(c2ccnc3ccccc23)CC1
Product: O=C(/C=C\C(F)(F)Cl)N1CCN(c2ccnc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7 %
Yield: 10 %

Procedure:
2-Diethoxyphosphoryl-1-[4-(4-quinolyl)piperazin-1-yl]ethanone (78.3 mg, 0.2 mmol) was dissolved in anhydrous THF (1 ml), NaH was added (12 mg of a 60% dispersion in mineral oil, 0.3 mmol) and the mixture was stirred for 30 minutes at room temperature. 2-Chloro-2,2-difluoro-acetaldehyde (0.3 mmol, the solution of step D) was added, the temperature was raised to 45° C. and stirring was continued for 3 hours. The mixture was diluted with water, basified with 0.1 NaOH and extracted with diethylether (2×). The combined organic phases were washed with 5% sodium bicarbonate solution, water, dried over magnesium sulfate and the solvent was removed under reduced pressure. The raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield (E)-4-chloro-4,4-difluoro-1-[4-(4-quinolyl)piperazin-1-yl]but-2-en-1-one (5 mg, 0.014 mmol, 7%) and (Z)-4-chloro-4,4-difluoro-1-[4-(4-quinolyl)piperazin-1-yl]but-2-en-1-one (7 mg, 0.02 mmol, 10%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C[Si](C)(C)N[Si](C)(C)C.[CH2:33]([Li])CCC.CCCCCC.BrC[CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:33])([CH2:13][CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)CCBr
Reactant: [Li]CCCC
Reactant: COC(=O)C(C)c1ccc(F)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(C)(CCC(C)(C)C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
A solution of the compound of Example 22A (11.75 g, 64.6 mmol) in tetrahydrofuran (30 mL) was added dropwise over 20 min to a −78° C. solution of lithium hexamethyldisilazide (previously prepared from hexamethyldisilazane (17.0 mL, 80.7 mmol) and n-butyllithium in hexane (2.5 M, 31.0 mL, 77.5 mmol)) in tetrahydrofuran (40 mL) and allowed to stir at that temperature for 1 h. The solution was then treated with 1-bromo-3,3-dimethylbutane (12.0 mL, 83.9 mmol), followed by stirring at −78° C. for 30 min, and then warming to 25° C. for 18 h. The solution was quenched by addition of saturated ammonium chloride solution (4 mL) and then concentrated in vacuo. The residue was diluted with ethyl acetate and water. The organic layer was extracted with water (2×), saturated NaCl solution and dried (Na2SO4). Concentration in vacuo afforded an oil, which was distilled under reduced pressure (90-93° C./0.3 mm Hg) to afford the product (4.85 g, 28%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 0.86 (s, 9 H) 1.03 (m, 2 H) 1.51 (m, 3 H) 1.86 (m, 1 H) 2.00 (m, 1 H) 3.65 (m, 3 H) 7.03 (m, 2 H) 7.27(m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][C:26]1[S:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:25][C:26]1[S:30][C:29]([C:31]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:32])=[CH:28][CH:27]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)s1
Yield: 45.3 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (16 mg, 0.050 mmol) obtained in Example 1, (3), 5-methylthiophene-2-carboxylic acid (14 mg, 0.101 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (21 mg, 0.055 mmol) were dissolved in DMF (2.0 mL), then the solution was added with triethylamine (10 mg, 0.101 mmol), and the mixture was stirred over night. The reaction mixture was treated in a conventional manner to give the title compound (10 mg, yield 45%) as white crystals.
Reaction SMILES: [CH:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.O.S(Cl)([Cl:21])=O>C(OCC)C.[Cl-].[Na+].O>[Cl:21][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCc2ccccc21
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: ClC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A 1 liter 3-necked flask equipped with a condenser, electronic thermocouple, mechanical stirrer and under a nitrogen atmosphere was charged with 1,2,3,4-tetrahydro-1-naphthol (34.3 g; 0.23 mol) in dry diethyl ether (420 ml). Pyridine (4.7 ml) was added and the flask was cooled to 16° C. in a bath of water and ice. A solution of thionyl chloride (50.7 ml; 0.70 mol) in ether (140 ml) was then added dropwise in 25 minutes and stirring continued overnight while allowing the bath to warm to ambient temperature. The reaction mixture was then poured into cold brine (400 g ice and 800 ml brine) and the organic phase was separated. The aqueous phase was extracted with diethyl ether (2×150 ml) and the combined organic extract was dried with sodium sulphate. Filtration and removal of solvent in vacuo gave 1,2,3,4-tetrahydro-1-chloronaphthalene (36.9 g) as an oil. This material was used without further purification.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15][CH3:16])[C@@H:13]([CH3:17])[CH2:12][O:11][C@H:10]1[C:18]([O:20]C)=O)C1C=CC=CC=1.[CH2:22]([NH2:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>>[CH2:22]([NH:29][C:18]([C@H:10]1[C@H:9]([OH:8])[C@@H:14]([O:15][CH3:16])[C@@H:13]([CH3:17])[CH2:12][O:11]1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCN
Reactant: COC(=O)[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1OCc1ccccc1
Agent: Cl
Product: CCCCCCCNC(=O)[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1O
Temperature: 90 °C
Reaction time: 12 h
Yield: 49.3 %

Procedure:
A mixture of methyl (2R,3R,4S,5S)-3-benzyloxy-4-methoxy-5-methyltetrahydro-2H-pyran-2-carboxylate (7 mg, 0.024 mmole) and heptylamine (0.1 ml, 0.68 mmole) was heated at 90° C. for 3 hr. The reaction mixture was adjusted to pH 3 with 0.1N aqueous HCl, and partitioned between ether (10 ml) and water (10 ml). The ether layer was dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. A solution of the resulting crude amide in MeOH (5 ml) was stirred under hydrogen atmosphere in the presence of Pd-black (5 mg) at room temperature for 12 hr. The catalyst was removed by filtration and washed with methanol (2 ml×2). The combined filtrate and washings were evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel using AcOEt/n-hexane (4:6) as an eluent to give (2R,3R,4S,5S)-N-heptyl-3-hydroxy-4-methoxy-5methyltetrahydro-2H-pyran-2-carboxamide (3.4 mg, 50% yield) as an oil; FAB-MS: m/z 288 (MH+). 1H-NMR (CDCl3)d: 0.91 (3H,t,J=6.5 Hz), 1.05 (3H,d,J=7 Hz), 1.25 (10H,br.s), 2.2 (1H, m), 3.10-3.6 (7H,br.m), 3.3 (3H,s), 3.81 (1H,dd,J=2.5 & 12 Hz), 8.0 (1H,br.s).
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[O:20][CH2:19][CH2:18][N:17](CC3C=CC=CC=3)[CH2:16]2)=[CH:11][CH:10]=1>ClC(Cl)C>[ClH:1].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc([C@H]2CN(Cc3ccccc3)CCO2)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Cl
Product: Fc1ccc([C@H]2CNCCO2)cc1
Yield: 73 %

Procedure:
1-Chloroethyl chloroformate was added to a solution of (2S)-2-(4-fluorophenyl)-4-(benzyl)morpholine (9.05 g) in dichloroethane (160 ml) at 70° C. After the reaction mixture was refluxed for 2 hrs, the solvent was evaporated under reduced pressure. Methanol (10 ml) was added to the residue, and then the mixture was refluxed for 30 min. The solvent was evaporated and the precipitate was collected by filtration to give (2S)-2-(4-fluorophenyl)morpholine hydrochloride (5.3 g, 73%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[NH:10][C:11](=[O:20])[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])=[CH:5][CH:4]=1.[Sn](Cl)[Cl:31]>>[ClH:31].[NH2:27][C:23]1[CH:22]=[C:21]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:10][C:11](=[O:20])[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:26]=[CH:25][CH:24]=1
Reactant: Cl[Sn]Cl
Reactant: COc1ccc(C(NC(=O)C(C)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Product: COc1ccc(C(NC(=O)C(C)c2ccccc2)c2cccc(N)c2)cc1
Product: Cl
Yield: 81.4 %

Procedure:
In a similar manner to that described in Example (47b), N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-2-phenylpropionamide (2.37 g) [prepared as described in step (a) above] and tin (II) chloride (5.76 g) were reacted, to afford the title compound (1.96 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH2:14]C2C=CC(C(C)(C)C)=CC=2)=O)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(O[CH:28](OCC)[N:29](C)[CH3:30])C.C([OH:37])C>C(=O)=O>[CH3:28][N:29]([CH:14]=[CH:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[CH:6][CH:7]=1)=[O:37])[CH3:30]
Reactant: CC(C)(C)c1ccc(CC(=O)Cc2ccc(C(C)(C)C)cc2)cc1
Reactant: CCOC(OCC)N(C)C
Reactant: CCO
Agent: O=C=O
Product: CN(C)C=CC(=O)c1ccc(C(C)(C)C)cc1

Procedure:
To 4-(1,1-Dimethylethyl)phenylmethyl ketone (5 g) in absolute ethanol (50 ml) heated to 80° C. with stirring was added N,N-dimethylformamide diethyl acetal (5.01 g) in absolute ethanol (2.5 ml) dropwise over 5 minutes, heated under reflux with stirring overnight and the reaction followed by tlc. The excess ethanol was removed under reduced pressure to give a brown oil which was cooled in cardice to give a yellow solid. The product was recrystallised from petroleum ether 40°-60° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[N:5][CH:4]=1.[H-].[Na+].[CH2:16](I)[CH:17]=[CH2:18]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[N:10]2[CH2:18][CH:17]=[CH2:16])=[N:5][CH:4]=1
Reactant: C=CCI
Reactant: COc1cnc2ccc(=O)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)ccc2ncc(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
7-(Methoxy)-1,5-naphthyridin-2(1H)-one (5.958 g, 33.852 mmol) was suspended in dry DMF (100 ml) under argon at rt, and the stirred suspension was treated with sodium hydride (2.98 g, 60% suspension in oil, 74.48 mmol) and stirred at rt for 0.5 h. Allyl iodide (6.88 ml, 74.475 mmol) was then added. The reaction was stirred at rt for 0.5 h and then the mixture was diluted with water to 300 ml and extracted with DCM (3×300 ml). The DCM extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give a brown gum which was purified by chromatography on silica gel using a 0-10% MeOH/DCM gradient to provide the desired compound (4.096 g, 56%). Mixed fractions could be triturated with diethyl ether to provide further compound (0.95 g, 13%).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)cc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (6.70 g, 28.2 mmol) in CH2Cl2 (100 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 1-chloro-4-((E)-2-nitro-vinyl)-benzene (4.97 g, 27.1 mmol) and trifluoroacetic acid (0.31 g, 2.7 mmol) in CH2Cl2 (150 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:4) afforded 6.75 g (79%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([CH3:31])=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1.[CH:38](=O)[CH3:39]>>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH2:38][CH3:39])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([CH3:31])=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1
Reactant: CC=O
Reactant: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(/C=C3\SC(=O)N([C@@H]4CCNC[C@H]4F)C3=O)cc12
Product: CCN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(c3)c(C)nn4Cc3ccc(Cl)cc3C(F)(F)F)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-3-[(trans)-1-ethyl-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-3-[(trans)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 333) and acetaldehyde following General Procedure R2.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].[Cl:19][C:20]1[CH:25]=[C:24]([C:26](Cl)=[O:27])[CH:23]=[CH:22][N:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([NH:13][C:12]2[CH:14]=[CH:15][C:9]([CH3:8])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[O:27])[CH:23]=[CH:22][N:21]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1[N+](=O)[O-]
Yield: 26.8 %

Procedure:
Triethylamine (31.8 ml) was added to a stirred mixture of 4-methyl-3-nitroaniline (15.8 g), 2-chloropyridine4-carbonyl chloride (20 g) and methylene chloride (1 liter) and the resultant mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated, washed with a saturated aqueous sodium bicarbonate solution and with methylene chloride and dried under vacuum at 40° C. There was thus obtained 2-chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide (10.2 g). The organic filtrate was washed with a saturated aqueous sodium bicarbonate solution, dried (MgSO4) and evaporated. The residue was triturated under methylene chloride and the resultant solid was isolated and dried under vacuum at 40° C. There was thus obtained a second crop (8.13 g) of 2-chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide; NMR Spectrum: (DMSOd6) 2.48 (s, 3H), 7.51 (d, 1H), 7.86 (m, 1H), 7.96 (m, 2H), 8.49 (m, 1H), 8.64 (m, 1H), 10.85 (s, 1H); Mass Spectrum: M+H+ 292 and 294.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@:20]([O:51][CH3:52])([NH:21][C:22](=[O:50])[C:23](=[N:29][O:30]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[C:19](=[O:53])[N:10]2[C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(=O)(O)[O-].[Na+]>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@@:20]([NH:21][C:22](=[O:50])[C:23](=[N:29][OH:30])[C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)([O:51][CH3:52])[C:19](=[O:53])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CO[C@@]1(NC(=O)C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccco2)C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CO[C@@]1(NC(=O)C(=NO)c2ccco2)C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@@H]21

Procedure:
t-Butyl (6R,7S)-3-acetoxymethyl-7-methoxy-7-[2-triphenylmethoxyimino-2-(fur-2-yl)-acetamido]-ceph-3-em-4-carboxylate (syn isomer) (713.3 mg, 0.966 mmole) was treated with trifluoroacetic acid (10 ml) and anisole (5 ml) for a total of 40 mins. and then added slowly to rapidly stirred saturated aqueous sodium bicarbonate (600 ml.). The mixture was extracted with ethyl acetate (2×150 ml), covered with ethyl acetate (200 ml), and adjusted to pH 2 with orthophosphoric acid. The organic layer was combined with the ethyl acetate wash (200 ml) of the aqueous layer, dried, and evaporated to a brown foam. Chromatography on three 40 × 20 cm. preparative-layer plates in chloroform-methanol-formic acid (90:16:2) provided a sample of the title compound as a pale-yellow foam containing ca 21/2 mole-equivalents water (i.r. and microanalysis) (137 mg, 0.283 mmole, 29%) paper chromatography Rf 0.26, Rf/Rf cephaloram 0.58, λmax (pH 6 buffer) 272.5 nm (ε 16,400).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[C:6]([O:15]C)=[N:5]2.Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[C:6]([OH:15])=[N:5]2
Reactant: COc1nc2cc(Cl)ccc2n2cnnc12
Agent: Cl
Solvent: CC(=O)O
Product: Oc1nc2cc(Cl)ccc2n2cnnc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture consisting of 3.4 g. (0.014 mole) of 7-chloro-4-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, 35 ml. of 1N hydrochloric acid and 105 ml. of glacial acetic acid was refluxed for a period of 2.5 hours. Upon completion of this step, the reaction mixture was cooled to room temperature and poured over ice/water. The resulting mixture was then stirred for a period of 20 minutes, filtered and the recovered solid product washed with water and air-dried to constant weight to ultimately afford 2.6 g. (87%) of pure 7-chloro-4-hydroxy-[1,2,4]triazolo[4,3-a]qunioxaline, m.p. >300° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[C:6]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:7]=2[O:8][C:9]=1[CH3:10])=O.[NH2:18][C:19]([NH2:21])=[S:20]>C(O)C>[ClH:1].[NH2:21][C:19]1[S:20][CH:2]=[C:3]([C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:7]=3[O:8][C:9]=2[CH3:10])[N:18]=1
Reactant: NC(N)=S
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1C(=O)CCl
Solvent: CCO
Product: Cc1oc2c([N+](=O)[O-])cccc2c1-c1csc(N)n1
Product: Cl
Yield: 91.6 %

Procedure:
A mixture of 3-chloroacetyl-2-methyl-7-nitrobenzo[b]furan (431 mg) and thiourea (194 mg) in ethanol (10 ml) was refluxed for 1.5 hours. The separated solid was collected, washed with ethanol and dried to give 3-(2-aminothiazol-4-yl)-2-methyl-7-nitrobenzo[b]furan hydrochloride (485 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19](Br)=[CH:20][CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH:38]=[CH2:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35](/[CH:38]=[CH:39]/[C:19]2[CH:18]=[C:17]3[C:22]([C:14]([CH:11]4[CH2:12][CH2:13][N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[CH2:9][CH2:10]4)=[N:15][NH:16]3)=[CH:21][CH:20]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(Br)ccc23)CC1
Reactant: C=CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Reaction time: 16 h
Yield: 66.1 %

Procedure:
A mixture of [4-(6-bromo-1H-indazol-3-yl)-piperidin-1-yl]-acetic acid tert butyl ester (1.34 g, 3.40 mmol), 4-vinyl-piperidine-1-carboxylic acid tert-butyl ester (0.75 g, 3.57 mmol), triethylamine (1.4 ml, 10.2 mmol), palladium (ii) acetate (0.050 g, 0.22 mmol) and tri(o-tolyl)phosphine (0.210 g, 0.6 mmol) in DMF (60 ml) was stirred at 120° under nitrogen for 16 h. The mixture was evaporated in vacuo and purified by flash chromatography on silica gel (Merck 9385), eluant ethyl acetate:cyclohexane:triethylamine (50:50:2→100:0:2), to give the title compound as a yellow solid (1.18 g, 66%).
Reaction SMILES: ONC(=O)C=CC1C=CN(S(CC2C=CC=CC=2)(=O)=O)C=1.[CH3:22][N:23]([CH3:50])[C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]2[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]([NH:42][O:43]C3CCCCO3)=[O:41])=[CH:34]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1>CO.O>[CH3:50][N:23]([CH3:22])[C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:33]2[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]([NH:42][OH:43])=[O:41])=[CH:34]2)(=[O:31])=[O:32])=[CH:28][CH:29]=1
Reactant: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Agent: O=C(C=Cc1ccn(S(=O)(=O)Cc2ccccc2)c1)NO
Solvent: O
Solvent: CO
Product: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NO)c2)cc1

Procedure:
The method used for preparation of this compound is analogous to the method described for compound 2. Starting materials: (E)-3-[1-(4-dimethylamino-benzene sulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (compound A4) (0.200 g), methanol/water 3/2 (50 ml), amberlyst IR15 (0.402 g). Reaction conditions: room temperature, 34 hours.