Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].[C:26]([O:30][C:31](=[O:43])[NH:32][CH2:33][C:34]1[CH:39]=[C:38]([NH2:40])[CH:37]=[CH:36][C:35]=1[C:41]#[N:42])([CH3:29])([CH3:28])[CH3:27].[F:44][C:45]1[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[CH:49][C:46]=1[CH:47]=O.C[Si]([C:61]#[N:62])(C)C>O.C(OCC)(=O)C.C1COCC1>[C:26]([O:30][C:31](=[O:43])[NH:32][CH2:33][C:34]1[CH:39]=[C:38]([NH:40][CH:47]([C:61]#[N:62])[C:46]2[CH:49]=[C:50]([O:55][CH3:56])[C:51]([O:53][CH3:54])=[CH:52][C:45]=2[F:44])[CH:37]=[CH:36][C:35]=1[C:41]#[N:42])([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1cc(F)c(C=O)cc1OC
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ccc1C#N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c(C(C#N)Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)cc1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 85.1 %

Procedure:
To a mixture of Yb(OTf)3(0.124 g) and THF (5 mL) there were added (5-amino-2-cyanobenzyl)carbamic acid t-butyl ester (Example (1g))(0.494 g), 2-fluoro-4,5-dimethoxybenzaldehyde (0.368 g), MS3A (1 g) and trimethylsilyl cyanide (533 mg) in that order under a nitrogen atmosphere, and the mixture was stirred at room temperature for 14 hours. Ethyl acetate (100 mL) and water (50 mL) were added to the mixture and filtration was performed with Celite. After sufficiently shaking the mixture, the organic layer was separated off and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (0.749 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:5][C:6]3[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12](O)=[O:13])[C:8](=[O:22])[C:7]=3[O:23][C:24]=2[CH:25]=[CH:26][CH:27]=1.[CH3:28]N1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C([O:61][C@@H:62]([CH2:70][O:71][CH2:72][CH3:73])[CH2:63][N:64]1[CH:68]=[CH:67][C:66]([NH2:69])=[N:65]1)C>O1CCCC1.O>[CH:16]1([CH2:15][C@H:11]([N:9]2[CH2:10][C:6]3[CH2:5][C:4]4[C:3]([O:2][CH3:1])=[CH:27][CH:26]=[CH:25][C:24]=4[O:23][C:7]=3[C:8]2=[O:22])[C:12]([NH:69][C:66]2[CH:67]=[CH:68][N:64]([CH2:63][C@@H:62]3[CH2:70][O:71][C:72]([CH3:73])([CH3:28])[O:61]3)[N:65]=2)=[O:13])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Reactant: CN1CCOCC1
Reactant: CCOC[C@@H](Cn1ccc(N)n1)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)C1
Temperature: 90 °C
Yield: 65.8 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (Example 7, step 2) (150 mg, 0.40 mmol), in tetrahydrofuran (5 mL) was treated with commercially available N-methylmorpholine (0.11 mL, 1.01 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (384 mg, 1.01 mmol) and 1-((R)-2,3-diethoxy-propyl)-1H-pyrazol-3-ylamine (96 mg, 0.48 mmol) (prepared following the procedure described in WO2009127546). The mixture was heated in a sealed tube was heated for 24 hours at 90° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-3-cyclohexyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionamide (145 mg, 65.3%), as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][NH:18][C:17](=[O:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][C:29]([Cl:35])=[CH:30][CH:31]=2)[N:26]=1>CN(C=O)C.O>[Cl:35][C:29]1[CH:28]=[C:27]2[C:32]([CH:33]=[CH:34][C:25]([CH2:24][N:18]3[CH2:19][CH:15]([C:9]4[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[CH:8]=4)[CH2:16][C:17]3=[O:20])=[N:26]2)=[CH:31][CH:30]=1
Reactant: ClCc1ccc2ccc(Cl)cc2n1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2CC(=O)N(Cc3ccc4ccc(Cl)cc4n3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[3-Cyclopentyloxy-4-methoxyphenyl]-2-pyrrolidinone (1.00 g, 3.63 mmol, 1.0 eq) was added to a room temperature suspension of (145 mg, 3.63 mmol, 1.0 eq) NaH (60% oil dispersion) in 30 ml of anhydrous DMF. After stirring at room temperature for 1 hour, (0.77 g, 3.63 mmol, 1.0 eq) 2-chloromethyl-7-chloroquinoline was added, and the reaction mixture was allowed to stir at room temperature for 60 hours. The reaction mixture was then diluted with 250 mL H2O and extracted with ethyl acetate. The ethyl acetate extract was washed twice with H2O, once with brine, dried over Na2SO4 and concentrated to yield a yellow oil. Silica gel chromatography eluting with 5% CH3OH/CH2Cl2 followed by recrystallization from ethyl acetate-hexane yielded 0.61 g, 37%, of white crystals. M.P.: 106°-107° C. Elemental Analysis Calc'd for C26H27N2O3Cl: Calc'd: C, 69.15; H, 6.03; N, 6.21. Found: C, 69.22; H, 5.75; N, 615.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].[NH4+:16]>>[N+:13]([C:11]1[CH:12]=[C:3]2[C:4](=[CH:9][CH:10]=1)[C:5](=[O:6])[NH:16][CH2:2]2)([O-:15])=[O:14]
Reactant: [NH4+]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Product: O=C1NCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of methyl 2-(bromomethyl)-4-nitrobenzoate in ammonium solution (7 N in methanol, 5 mL) was stirred at room temperature for 2 hours and concentrated in vacuum to obtain a yellow solid. This crude solid was triturated with ethyl acetate (15 mL) and was then cooled at −20° C. The mixture was filtered to obtain the product 5-nitroisoindolin-1-one as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.04 (br s, 1H), 8.48 (d, 1H, J=2.0 Hz), 8.25 (dd, 1H, J=2.0 Hz, 8.4 Hz), 7.91 (d, 1H, J=8.4 Hz), 4.51 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([CH:12]2[CH2:14][CH2:13]2)([CH3:11])[CH:9]=O)=[CH:4][CH:3]=1.[NH2:15][OH:16].[Cl-].[Na+].C(OC(C)C)(=O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([CH:12]2[CH2:14][CH2:13]2)([CH3:11])[CH:9]=[N:15][OH:16])=[CH:4][CH:3]=1
Reactant: NO
Reactant: C[C@](C=O)(c1ccc(Br)cc1)C1CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: C[C@](C=NO)(c1ccc(Br)cc1)C1CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a 500 mL reactor is charged the crude solution of (R)-2-(4-bromophenyl)-2-cyclopropylpropanal (7, 230 g, 11.9 wt %, 108.1 mmol, 1.00 equiv). The batch is reduced to 75 mL (3 vols) via vacuum distillation (external temperature NMT 55° C.). To the batch is charged ethanol (denatured, 78.9 g, 100 mL, 4 vols). The batch is reduced to 75 mL (3 vols) via vacuum distillation (external temperature NMT 55° C.). To the batch is charged ethanol (denatured, 39.5 g, 50 mL, 2 vols). The batch temperature is adjusted to an internal temperature of 10±5° C. To the batch is charged 50 wt % Hydroxylamine (10.7 g, 162.2 mmol, 1.50 equiv) at a rate to maintain the internal temperature of the batch <30° C. The batch is then agitated at an internal temperature of 20±5° C. for 2 h. An HPLC sample is removed to determine conversion (target >97 A % conversion 220 nm, for this batch: >99.5 A % conversion). To a separate vessel (vessel 2) is prepared the 5 wt % aqueous sodium chloride solution by dissolving sodium chloride (7.5 g) in water (142.5 g). To the batch is charged isopropyl acetate (157 g, 180 mL, 7 vols) and 5 wt % aqueous sodium chloride (75 g, ˜3 vols, vessel 2). The batch is agitated for 20 min and then the layers are allowed to settle. The aqueous layer is cut. To the batch is charged 5 wt % aqueous sodium chloride (75 g, ˜3 vols, vessel 2). The batch is agitated for 20 min and then the layers are allowed to settle. The aqueous layer is cut. The batch volume is adjusted to 2-3 vols (50-75 mL) via vacuum distillation (external temperature NMT 55° C.). To the batch is charged acetonitrile (39.3 g, 50 mL, ˜2 vols). The batch volume is adjusted to 2 vols (50-75 mL) via vacuum distillation (external temperature NMT 55° C.). The batch was drained and the reactor rinsed with acetonitrile (3.9 g, 5 mL). The rinse is combined with the original batch and the resulting solution reduced to ˜50 mL via vacuum distillation. The mass of the resulting solution: 44.4 g and the Proton NMR wt % assay (with dimethyl fumarate as an internal standard) is 65 wt % (28.9 g, 99.5% yield) of (R)-2-(4-bromophenyl)-2-cyclopropylpropanal oxime (8). The solution is used as is for the following step.
Reaction SMILES: [Na].[NH3:2].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:12]([O:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[C:13]([C:36]#[N:37])[C:14](=[C:17]([O:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C:18]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[C:15]#[N:16]>C(O)CC>[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:12]([O:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[C:13]2[C:14](=[C:17]([O:30][CH2:31][CH2:32][CH:33]([CH3:34])[CH3:35])[C:18]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:27])[CH3:28])=[CH:22][CH:21]=1)[C:15](=[NH:2])[NH:16][C:36]2=[NH:37]
Reactant: N
Reactant: CC(C)CCOc1c(C#N)c(C#N)c(OCCC(C)C)c(Sc2ccccc2N)c1Sc1ccc(C(C)(C)C)cc1
Agent: [Na]
Solvent: CCCO
Product: CC(C)CCOc1c(Sc2ccc(C(C)(C)C)cc2)c(Sc2ccccc2N)c(OCCC(C)C)c2c1C(=N)NC2=N
Reaction time: 20 h
Yield: 75.2 %

Procedure:
To a solution of sodium metal (0.6 g) in n-propyl alcohol (200 mL) was fed gaseous ammonia at a flow rate of 120 mL/min. at room temperature for 1 hour. Then, 27.0 g of 4-(2-aminophenylthio)-5-(4-tert-butylphenylthio)-3,6-diisopentoxyphthalonitrile was added and the mixture was stirred at 50~60° C. for 20 hours. After cooling, the reaction mixture was worked up in the same manner as in Example 1 to provide 20.9 g (yield 75.2%) of 5-(2-aminophenylthio)-6-(4-tert-butylphenylthio)-1,3-diimino-4,7-diisopentoxyisoindoline of the following chemical formula. ##STR12##
Reaction SMILES: Cl.O1CCCCC1[O:8][CH2:9][CH2:10][C:11]1([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12]1>CCOCC.CO.C(OC(C)C)(C)C.CCOCC>[OH:8][CH2:9][CH2:10][C:11]1([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12]1
Reactant: Clc1ccc(C2(CCOC3CCCCO3)CCNC2)cc1Cl
Agent: Cl
Solvent: CO
Solvent: CC(C)OC(C)C
Solvent: CCOCC
Product: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
A solution of hydrogen chloride in ether is added to a solution of 3.4 g of 3-tetrahydropyranyloxyethyl-3-(3,4-dichlorophenyl)pyrrolidine in 20 ml of methanol until the pH is 1. The mixture is stirred for half an hour at room temperature and concentrated to dryness, the residue is taken up in water, rendered basic with a solution of sodium hydroxide and extracted with dichloromethane and the extract is washed with a saturated solution of NaCl, dried over Na2SO4 and evaporated to dryness to give an oil. This oil is taken up in 20 ml of an isopropyl ether/ether mixture (50/50 v/v). After stirring and filtration, the product is washed with ethyl ether and dried under vacuum over P2O5. 2.6 g of the expected product are isolated.
Reaction SMILES: C1COCC1.[C:6]1([CH3:14])[CH:11]=[CH:10][C:9]([Mg]Br)=[CH:8][CH:7]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](Cl)=[CH:19][CH:18]=1.C1(C)C=CC=CC=1>CCCCCC>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:9]2[CH:10]=[CH:11][C:6]([CH3:14])=[CH:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(Cl)cc1
Reactant: Cc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1ccc(-c2ccc(C)cc2)cc1
Reaction time: 24 h
Yield: 92 %

Procedure:
Using a THF solution of p-tolylmagnesium bromide (1.18 mL, 1.02 M, 1.2 mmol) and 1-methoxy-4-chlorobenzene (142.6 mg, 1.0 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 60° C. for 24 hours in the same manner as in Example 2. After performing silica gel column chromatography (toluene=15, 30 and 50% in hexane), the above compound was obtained as a white solid (0.182 g, yield=92%, purity=>99% (GC analysis)).
Reaction SMILES: C(NC(C)C)(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].[C:13]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C1COCC1>[CH2:29]([O:28][C:26]([C:23]1([CH2:12][CH2:11][CH:10]=[CH2:9])[CH2:24][CH2:25][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:21][CH2:22]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CCCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
A mixture of THF (160 mL) and diisopropyl amine (9.92 mL, 70.8 mmol, 1.2 eq) was cooled to −78° C. and a 2.5 M solution of n-BuLi in heptanes (28.3 mL, 70.8 mmol, 1.2 equiv.) was added slowly. The solution was stirred for 15 min, warmed to 0° C. for 20 min and cooled back to −78° C. Ethyl N-Boc-piperidine-4-carboxylate (11 mL, 59 mmol, 1 eq.) in 10 mL of THF was added drop-wise and stirred for 40 min before it was warmed to rt. The reaction mixture was stirred for 12 h, transferred to a separatory funnel, quenched with 500 mL of water and extracted with ethyl acetate (2×300 mL). The combined organics were dried over Na2SO4 and concentrated under vacuum to give the title compound as an yellow oil (13.9 g, 76%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([CH2:24][NH2:25])[CH:21]=[CH:22][CH:23]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Cl:11][C:4]1[CH:3]=[C:2]([NH:25][CH2:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[CH:19]=2)[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=1
Reactant: NCc1cccc(-c2ccccn2)c1
Reactant: NC(=O)c1cnc(Cl)cc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(Cl)cc1NCc1cccc(-c2ccccn2)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 43.5 %

Procedure:
To a solution of 4,6-dichloronicotinamide (73 mg, 0.38 mmol) in NMP (0.75 mL) was added (3-(pyridine-2-yl)phenyl)methanamine (77 mg, 0.42 mmol) and DIPEA (0.22 mL, 1.33 mmol). After stirring at 80° C. for 15 h, the mixture was added water, the resulting precipitate was collected by filtration to give 6-chloro-4-(3-(pyridine-2-yl)benzylamino)nicotinamide (56 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CCOCC>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cc1ccc(Br)cc1
Reaction time: 2.5 h
Yield: 99.3 %

Procedure:
To a solution of 4-Bromo-phenyl-acetic acid (8.6 g, 40 mmol) in DMF (80 mL) is added K2CO3 (6.16 g, 44 mmol) followed by methyl iodide (2.8 mL, 45 mmol). The resulting mixture is stirred for 2.5 hours, then diluted with ether, washed with water and brine, dried over MgSO4 and concentrated to give 9.1 g of the title compound as an oil. This material is used without further purification. 1H NMR (CDCl3) d 3.58 (s, 2H), 3.69 (s, 3H), 7.13 (d, J=8 Hz, 2H), 7.43 (d, J=8 Hz, 2H). MS (EI) m/z 228/230 (M+) Br pattern.
Reaction SMILES: BrC1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:19][CH2:20][N:21]1[CH2:25]C[CH2:23][CH2:22]1.C([Sn](CCCC)(CCCC)[C:31]1[O:32][C@H:33]([CH2:43]OOC)[C@@H:34](OOC)[C@H:35](OOC)[CH:36]=1)CCC>>[O:32]1[CH:31]=[CH:36][CH2:35][CH2:34][CH:33]1[C:43]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH:19]1[CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=C[C@@H](OOC)[C@H](OOC)[C@@H](COOC)O1
Reactant: O=C(c1ccccc1)n1cc(CCN2CCCC2)c2cc(Br)ccc21
Product: CN1CCC(c2cn(C(=O)c3ccccc3)c3ccc(C4CCC=CO4)cc23)C1

Procedure:
3-(2-Pyrrolidinylethyl)-5-(3,4,6-trimethoxyglucal-1-yl)-1-benzoylindole: (80%), from 5-bromo-3-(2-pyrrolidinylethyl)-1-benzoylindole (Example 5c) and 2-tributylstannyl-tri-O-methoxy-D-glucal (Example 8).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[C:20](=[N:27][O:28][CH3:29])[C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)[C@H:4]2[S:3]1.C(O)(=O)C>O1CCCC1.[Zn]>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[C:20](=[N:27][O:28][CH3:29])[C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)[C@H:4]2[S:3]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12)c1csc(N)n1
Agent: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12)c1csc(=N)[nH]1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem4-carboxylate (syn isomer), which can be represented as 2,2,2-trichloroethyl 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (0.1 g.) in tetrahydrofuran (2 ml.) and glacial acetic acid (0.25 ml.) was added zinc powder (0.1 g.) all at once with stirring at keeping the temperature below 25° C. in an ice-bath and then the mixture was stirred for 1 hour at room temperature. To the reaction mixture was further added zinc powder (0.1 g.) and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was filtered, and the insoluble material was washed with a small amount of tetrahydrofuran. After the filtrate and the washing were combined together, the solvents were distilled off. To the residue were added 5% aqueous sodium bicarbonate solution and ethyl acetate so that the aqueous layer became pH 7 to 8, and the mixture was filtered, and then the aqueous layer was separated. The aqueous layer was adjusted to pH 2 to 3 with 2N hydrochloric acid and then concentrated slightly. Thus obtained aqueous layer was subjected to column chromatography (non-ionic adsorption resin, Diaion HP 20 prepared by Mitsubishi Chemical Industries) and the column was washed with water and then eluted with 20% methanol and 40% methanol in turn. The eluates containing the object compound were collected and then lyophilized to give white powder of 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (0.015 g.), mp 230° to 235° C. (dec.).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][NH:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.C([N-:14]C(C)C)(C)C.[Li+].O.O.O.C([O-])(=O)C.[Na+].N[O:28][S:29]([OH:32])(=O)=O>O1CCCC1>[S:29]([C:2]1[S:1][C:9]2[CH:8]=[CH:7][NH:6][C:5](=[O:10])[C:4]=2[CH:3]=1)(=[O:32])(=[O:28])[NH2:14]
Reactant: CC(C)[N-]C(C)C
Reactant: O=c1[nH]ccc2sccc12
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1cc2c(=O)[nH]ccc2s1
Temperature: -70 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a suspension of thieno[3,2-c]pyridin-4(5H)-one (1.51 g, 10 mmol) in distilled tetrahydrofuran (20 ml), cooled to -70° C. and under a nitrogen atmosphere, was added dropwise 0.7 M lithium diisopropylamide in THF (36 ml, 25 mmol). After one hour, sulfur dioxide gas was bubbled over the surface of this suspension and the reaction was allowed to gradually warm to room temperature. The mixture was diluted with diethyl ether and the precipitated lithium sulfinate intermediate was collected (3.6 g). This salt was dissolved in water (25 ml) and sodium acetate trihydrate (5.4 g, 66 mmol) and hydroxylamine-O-sulfonic acid (2.5 g, 22 mmol) were added. After stirring for 16 hours, the precipitated product was collected by filtration. The product was purified by recrystallization from hot dimethyl sulfoxide by dilution with ethanol to give 1.35 g (59% yield); m.p. 300°-301° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:24][CH:23]=2)[C:18]([O:20]C)=[O:19])[CH3:16])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]([CH:17]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:26][CH:27]=2)[C:18]([OH:20])=[O:19])[CH3:16])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(OCCCNC(=O)OCC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)O)c2ccc(OCCCNC(=O)OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A mixture of methyl [{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino}(4-{3-[(ethoxycarbonyl)amino]propoxy]phenyl)acetate (0.45 g, 0.85 mmol) and 1N NaOH (4.2 ml, 4.23 mmol) in THF (5 ml) and methanol (5 ml) was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in water, neutralized with HCl to pH˜5-6 and extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to provide 0.36 g of [{[4-(2-butynyloxy)phenyl]-sulfonyl}(methyl)-amino}(4-{3-[(ethoxycarbonyl)amino]propoxy]phenyl)acetic acid as a solid. Yield 81.8%. Electrospray Mass Spec 519.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][C:24](OC)=[O:25].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][CH2:24][OH:25]
Reactant: COC(=O)CC1=C(C)/C(=C/c2ccc(S(C)(=O)=O)cc2)c2ccc(F)cc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1=C(CCO)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the ester from Step 1 (2.7 g, 7 mmol) in THF (20 mL) at 0° C. there was added diisobutyl aluminum hydride (1M) in toluene (17 mL, 17 mmol) and the mixture was stirred at 0° C. for 1 hour, then quenched with methanol (10 mL). Ethyl acetate and 1N aqueous HCl were added and after collection of the organic phase the aqueous phase was extracted once more with ethyl acetate. The combined organic extracts, after washing with water three times and drying over Na2SO4, afforded on evaporation a yellow residue which was triturated with ether to afford the title compound as a yellow solid, mp: 102-104° C.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([C:6](=[N:9][OH:10])[C:7]1=O)[CH:4]([CH3:13])[O:3]2.[NH2:14][NH2:15]>C(O)C>[CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([C:6](=[N:9][OH:10])[C:7]1=[N:14][NH2:15])[CH:4]([CH3:13])[O:3]2
Reactant: CC1OC2(C)CCC1C(=NO)C2=O
Reactant: NN
Solvent: CCO
Product: CC1OC2(C)CCC1C(=NO)C2=NN

Procedure:
A mixture of 1.83 g. (0.01 mole) 1,3-dimethyl-2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime and 0.35 ml. (0.011 mole) anhydrous hydrazine (98%) in 25 ml. absolute ethanol is refluxed under nitrogen at a bath temperature of 80° C. for 1 hour. Evaporation of the solvent gives 1,3-dimethyl-2-oxa-bicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone.