Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)([OH:3])=[O:2].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH2:19]([O:18][C:16]([CH2:15][O:2][C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)=[O:3])=[O:17])[CH3:20]
Reactant: O=C(O)c1cc2cccc(O)c2o1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COC(=O)c1cc2cccc(OCC(=O)OCC)c2o1
Yield: 78 %

Procedure:
2-Carboxy-7-hydroxybenzofuran and ethyl bromoacetate were reacted to give 2-(ethoxycarbonylmethoxycarbonyl)-7-(ethoxycarbonylmethoxy)benzofuran (yield: 78%, MS (m/z): 350 (M+), 305, 277, 249 and 219), which was then reacted with chlorosulfonic acid as in Example 1, yielding 2-(ethoxycarbonylmethoxycarbonyl)-4-chlorosulfonyl-7-ethoxycarbonylmethoxybenzofuran (yield: 68%, MS (m/z): 448 (M+), 413, 382 and 350). The obtained chlorosulfonyl compound was reacted with glycine ethyl ester hydrochloride as in Example 1 to give an ester compound (yield: 98%, MS (m/z): 515 (M+), 470, 442, 414 and 350), which was then hydrolyzed to give 2-carboxy-4-(N-carboxy-methylsulfamoyl)-7-(carboxymethoxy)benzofuran (colorless needles, yield: 83%). The physical constants are shown in Table 4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:12][C:13]([CH2:16][OH:17])=[N:14][CH:15]=1.[CH:23]1([CH:26]([C:33]2[CH:38]=[C:37](O)[N:36]=[CH:35][N:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH:23]1([CH:26]([C:33]2[CH:38]=[C:37]([O:17][CH2:16][C:13]3[CH:12]=[C:11]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[CH:15][N:14]=3)[N:36]=[CH:35][N:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1
Reactant: COc1ccc(F)c(-c2cnc(CO)cc2OCC(C)C)c1
Reactant: CCOC(=O)CC(c1cc(O)ncn1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cc(OCc2cc(OCC(C)C)c(-c3cc(OC)ccc3F)cn2)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of (5-(2-fluoro-5-methoxyphenyl)-4-isobutoxypyridin-2-yl)methanol (200 mg) and ethyl 3-cyclopropyl-3-(6-hydroxypyrimidin-4-yl)propanoate (155 mg) in toluene (9.4 mL) were added 1,1′-(azodicarbonyl)dipiperidine (264 mg) and tributylphosphine (261 μL), and the mixture was stirred at room temperature for 24 hr. Hexane/ethyl acetate (1:1) was added to the reaction mixture, the resulting precipitate was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (78 mg) as a colorless amorphous solid.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CON(C)[C:16]([C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)=[O:17]>>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1c(F)ccc(C(=O)O)c1F
Reactant: CON(C)C(=O)c1cnccn1
Product: Cc1c(F)c(C(=O)O)cc(C(=O)c2cnccn2)c1F

Procedure:
Starting materials: 2,4-difluoro-3-methylbenzoic acid (Intermediate 46) and N-methoxy-N-methylpyrazine-2-carboxamide.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:22]([O-])=O)=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH:5]=[C:6]([CH3:8])[CH:7]=1>[Pd].C(OCC)(=O)C>[NH2:22][C:3]1[C:2]([F:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1
Reactant: Cc1cc(F)c([N+](=O)[O-])c(NC2CCN(C3CCOCC3)CC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(F)c(N)c(NC2CCN(C3CCOCC3)CC2)c1
Temperature: 30 °C
Reaction time: 9 h
Yield: 69.1 %

Procedure:
A mixture of N-(3-fluoro-5-methyl-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (10 g), ethyl acetate (200 ml) and 10% Pd/C (1 g), was stirred at about 30° C. under hydrogen pressure for 9 hours. The catalyst was filtered and the filtrate concentrated. The residue was stirred with ethyl acetate (20 ml) and hexane (40 ml) for 1 hour at room temperature then filtered and the solid dried at 50° C. to give the title compound as a solid (6.3 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([CH:16]([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:17][CH2:18][OH:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.O>C(Cl)Cl>[CH:11]1([CH:16]([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:41])[CH3:40])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:17][CH:18]=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCO)C4CCCC4)c3)ncnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=O)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.6 %

Procedure:
To a solution of oxalyl chloride (0.108 mL, 1.28 mmol) in DCM (10.0 mL) at −78° C. was added DMSO (151 μL, 2.13 mmol). After stirring for 5 minutes, 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propan-1-ol (471 mg, 1.07 mmol) in DCM (3.00 mL) was added. The mixture was stirred for 30 minutes at −78° C. TEA (594 μL, 4.26 mmol) was then added. The resulting mixture was then allowed to warm to room temperature over the course of 30 minutes. Water was added, and the layers were separated. The organic layer was washed successively with 0.1 N HCl, water, saturated sodium bicarbonate solution, and brine, and was then dried over sodium sulfate and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient of 0-60% ethyl acetate in hexanes) afforded the product (384 mg, 82%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N+:32]=3[O-:37])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[CH2:42]([OH:45])[CH2:43][OH:44]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:44][CH2:43][CH2:42][OH:45])[N:18]=[C:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N+:32]=3[O-:37])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2cccc[n+]2[O-])nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Solvent: CC(=O)O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2cccc[n+]2[O-])nc1OCCO
Temperature: 80 °C

Procedure:
216 mg of 2-[4-(4-tert-butyl-phenylsulphonylamino)-6-chloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine 1-oxide were added to a solution of 46 mg of Na in pure ethylene glycol and the solution which slowly resulted was heated at 80° C. overnight. The solution was poured into aqueous acetic acid, the precipitate was extracted with ethyl acetate, triturated with ether and filtered off under suction. There was obtained 2-[4-(4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine 1-oxide as an amorphous mass which was dried in a high vacuum at 40° C. MS: (M+H)+ =567.4.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]2[CH:17]=[CH:18][N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:4]=2[C:3]1=[O:30].Br[C:32]1[C:41]([O:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=2[F:50])=[CH:40][C:35]2[NH:36][C:37](=[O:39])[NH:38][C:34]=2[CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC12CC3(C)OC(C)(CC(C)(O3)O1)P2C1C=CC=CC=1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:50][C:44]1[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:43]=1[O:42][C:41]1[C:32]([C:6]2[C:5]3[CH:17]=[CH:18][N:19]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:4]=3[C:3](=[O:30])[N:2]([CH3:1])[CH:7]=2)=[CH:33][C:34]2[NH:38][C:37](=[O:39])[NH:36][C:35]=2[CH:40]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Reactant: O=c1[nH]c2cc(Br)c(Oc3ccc(F)cc3F)cc2[nH]1
Agent: [Pd]
Agent: CC12CC3(C)OC(C)(CC(C)(O1)P3c1ccccc1)O2
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc5[nH]c(=O)[nH]c5cc4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
A suspension of 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (85.0 mg, 0.20 mmol), 5-bromo-6-(2,4-difluorophenoxy)-1,3-dihydro-2H-benzimidazol-2-one (74.5 mg, 0.218 mmol), potassium phosphate (0.10 g, 0.50 mmol), tris(dibenzylideneacetone)dipalladium (O) (5.0 mg, 0.006 mmol), and 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane (6.8 g, 0.0232 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was degassed with nitrogen for 5 min and stirred at 80° C. for 1 h. The reaction mixture was diluted with ethyl acetate and water and filtered over celite. The organic layer was separated, washed with brine, dried with magnesium sulfate, filtered, and concentrated to give a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (24 mg, 18%) as an off-white foam. LCMS calculated for C28H21F2N4O5S (M+H)+: m/z=563.1. found: 563.1.
Reaction SMILES: [C@]12(C)C(C)(C)C(CC1)CC2C([O:12][C@@H:13]([C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])[CH:14]([CH3:16])[CH3:15])=O.C([O-])([O-])=O.[K+].[K+]>CO>[I:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:13]([OH:12])[CH:14]([CH3:15])[CH3:16])=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=1
Reactant: CC(C)[C@@H](OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccc(I)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)[C@@H](O)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.5 %

Procedure:
(R)-1-(4-Iodo-2-nitrophenyl)-2-methyl-1-propyl (1S)-camphanate (0.41 g, 0.82 mmol) was dissolved in hot methanol (60 mL) and K2CO3 (0.22 g, 1.58 mmol) was added. The mixture was heated to reflux for one hour, cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography to yield (R)-1-(4-Iodo-2-nitrophenyl)-2-methyl-1-propanol (0.262 g, 100%) as a light yellow oil. 1H NMR was identical to that of the racemic alcohol.
Reaction SMILES: [CH2:1]([Li])CCC.C1COCC1.[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:32][C:33]1[C:45]([CH:46]=O)=[C:44]([F:48])[CH:43]=[CH:42][C:34]=1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].[Cl-].[NH4+]>C1COCC1>[F:32][C:33]1[C:45]([CH:46]=[CH2:1])=[C:44]([F:48])[CH:43]=[CH:42][C:34]=1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)c1ccc(F)c(C=O)c1F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [I-]
Solvent: C1CCOC1
Product: C=Cc1c(F)ccc(C(=O)OC(C)(C)C)c1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
At −78° C., 9.50 ml of 1.59 M n-butyl lithium-THF solution was added dropwise to 90 ml of THF solution containing 8.13 g of methyltriphenylphosphonium iodide. This was stirred at 0° C. for 10 minutes, cooled to −78° C. and then mixed with 2.44 g of tert-butyl 2,4-difluoro-3-formylbenzoate dissolved in 10 ml of THF. After 40 minutes thereof, this was stirred at room temperature for 1 hour, mixed with appropriate amounts of saturated ammonium chloride aqueous solution and purified water, extracted with ethyl acetate and then dried with anhydrous magnesium sulfate. After concentration, the thus formed residue was purified by a silica gel column chromatography to obtain 1.20 g (50%) of tert-butyl 2,4-difluoro-3-vinylbenzoate (Reference Example 5-1) from a hexane-ethyl acetate (50:1) eluate. ES−: 239
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([C:41](=[O:43])[CH3:42])[C:36]([O:38]CC)=O)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:28]=[C:29]2[C:30](=[CH:31][CH:32]=1)[N:33]=[CH:34][C:35]([C:41](=[O:43])[CH3:42])=[C:36]2[OH:38]
Reactant: CCOC(=O)C(=CNc1ccc(Br)cc1)C(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(=O)c1cnc2ccc(Br)cc2c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.9 %

Procedure:
To Dowtherm at 250° C. was added Ethyl 2-[(4-bromophenylamino)methylene]-3-oxobutanoate (3.4 g, 10.9 mmol) portionwise and the reaction mixture was stirred for 1.5 h. The reaction mixture was cooled to room temperature, diluted with hexanes and the resulting precipitate was filtered to afford the desired product (2.2 g, 76%) as a brown solid: ESI MS m/z 266 [C11H8BrNO2+H]+.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:8]2[CH2:7][C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]2=3)=[O:29])=[CH:31][CH:32]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc2c(c1)CNc1ccccc1O2
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Product: O=C(c1ccccc1)c1ccc(C(=O)N2Cc3ccccc3Oc3ccccc32)cc1

Procedure:
As described for Example 26, 10,11-dihydrodibenz[b,f][1,4]oxazepine is reacted with 4-(benzoyl)benzoyl chloride to give the product as an off-white, m.p. 103°-106° C.; Mass spectrum (CI), 406 (MH+).
Reaction SMILES: C(O[C@H:9]1[C@H:15]([OH:16])[CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C@@H:10]1[CH:11]=[O:12])C1C=CC=CC=1.[OH2:27].C(=O)([O-])[O-].[Ba+2].BrBr>O1CCOCC1>[CH2:20]([C@H:9]1[C@@H:15]([OH:16])[CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C@@H:10]1[C:11]([OH:12])=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C[C@@H]1[C@@H](OCc2ccccc2)[C@H](O)CN1C(=O)OCc1ccccc1
Reactant: O
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1[C@@H](Cc2ccccc2)[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 75 %

Procedure:
A solution of 3-O-benzyl-N-benzyloxycarbonyl-2,5-dideoxy-2,5-imino-D-lyxose (15) (900 mg, 2.54 mmol), in a 1:1 mixture of water and 1,4-dioxan (15 ml) containing barium carbonate (1.46 g, 7.62 mmol), was cooled to 0° C. and treated with bromine (298 μl, 5.33 mmol). After stirring for 24 hours excess bromine was destroyed by the dropwise addition of 10% sodium thiosulphate solution and the suspension acidified with 2M HCl (20 ml). The product was extracted into dichloromethane (4×50 ml), dried, filtered and evaporated. Purification by flash chromatography (ethyl acetate-hexane (1:1 to ethyl acetate) afforded (2S,3R,4R)-3-benzyl-N-benzyloxycarbonyl-4-hydroxyproline (738 mg, 75%) as a clear oil, [α]20D -3.7° (c, 0.88 in chloroform); νmax (film) 3400 (OH), 2950, 1680 (2×CO), 1425, 1360 and 1195 cm-1 ; 1H NMR δ 3.62-3.78 (2H, 2×dd, H-5); 4.21, 4.26 (2H, s, and bs, H-3, H-2); 4.49-4.69 (3H, m, CH2Ph); 5.06-5.18 (2H, 2×dd, CH2 -Z); 5.6 (2H, bs, 2×OH); 7.27-7.38 (10H, m, 2×H-Ph). m/z: 91 (100%), 310 (45%), 372 (M+H+, 30%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.Cl[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:27][O:26][C:24]1[CH:25]=[C:20]([C:16]2[CH:15]=[C:14]([CH2:13][N:1]3[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]3)[CH:19]=[CH:18][N:17]=2)[CH:21]=[C:22]([O:30][CH3:31])[C:23]=1[O:28][CH3:29]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1CCN(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl piperidine-4-carboxylate (514 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (969 mg) in acetonitrile (20 mL) was added potassium carbonate (452 mg). The mixture was stirred at room temperature for 4 hours and evaporated. The residual oil was subjected to a column of silica gel and eluted using hexane-ethyl acetate (2:1) and then chloroform-methanol (40:1). Fractions containing the product were collected and evaporated to give the title compound as white prisms.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=1[NH:19][NH2:20]>>[NH2:9][C:8]1[N:19]([C:12]2[C:11]([Cl:10])=[CH:16][C:15]([Cl:17])=[CH:14][C:13]=2[Cl:18])[N:20]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Product: N#Cc1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1N

Procedure:
The title compound was prepared as an orange solid, m.p. 208.5-209.5° C. by the procedure of Preparation A starting with ethoxymethylenemalononitrile and 2,4,6-trichlorophenylhydrazine.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[ClH:18].[H][H].C>[Pd].CO>[ClH:18].[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)NC1CCNCC1
Reaction time: 1 h

Procedure:
10% w/w Palladium on charcoal (1.5 g) was added to a solution of the product from step (i) (10.0 g), 1 molar hydrochloric acid (21.5 ml) and methanol (150 ml) and the mixture hydrogenated at room temperature and pressure until the theoretical amount of hydrogen had been taken up. Charcoal was added, the mixture stirred for 1 hour then filtered through diatomaceous earth and the filtrate evaporated to dryness giving 4-acetylaminopiperidine hydrochloride, 8.64 g, as a sticky foam: NMR (CDCl3 +d6DMSO). δ 9,72(1H,b), 9.02(1H,b), 7.40(1H,bd), 3.87(1H,m), 3.30(2H,m), 2.81(2H,m), 1.86(4H,m), 1.80(3H,s); m/e 143 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:22]([NH:23][C:24](=[O:71])[C:25]([C:46]3[N:47]=[C:48]([NH:51][C:52]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[S:49][CH:50]=3)=[N:26][O:27][CH:28]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH3:29])[C:21](=[O:72])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10].[I-:73].[Na+]>CC(C)=O>[I:73][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:22]([NH:23][C:24](=[O:71])[C:25]([C:46]3[N:47]=[C:48]([NH:51][C:52]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[S:49][CH:50]=3)=[N:26][O:27][CH:28]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH3:29])[C:21](=[O:72])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10]
Reactant: [I-]
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)C(=NOC(C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)CS[C@@H]3C(NC(=O)C(=NOC(C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1

Procedure:
280 mg (0.28 mmol) of p-methoxybenzyl 3-chloromethyl-7-{(2-tritylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-ethoxyimino)acetamido}-ceph-3-em-4-carboxylate-syn isomer was dissolved in 3 ml of acetone, and 1.0 ml of acetone solution containing 60 mg (0.4 mmol) of sodium iodide was added to the resulting solution at room temperature and reacted for 40 minutes. After the reaction, the solvent was distilled out, and methylene chloride was added to the resulting residue, the insoluble materials were filtered off, and the remaining filtrate was concentrated under reduced pressure, to obtain p-methoxybenzyl 3-iodomethyl-7- {2-(2-tritylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-ethoxyimino)acetamido}-ceph-3-em- 4-carboxylate-syn isomer. To this was added 52 mg (0.34 mmol) of 1-(2-fluoroethyl)-4-pyridothione, and the resulting mixture was dissolved in 3 ml of chloroform and reacted for 1 hour at room temperature. After the reaction, the chloroform was distilled out under reduced pressure, and the residue was purified by silicagel-chromatography (chloroform/ethanol=10/1) and dissolved in 0.8 ml of anisol, and then, 4.0 ml of trifluoroacetic acid was added thereto, while cooled with ice, and reacted for 1 hour. After the reaction, isopropylether was added to the reaction solution to form a precipitate. After dried, 190 mg of a powder was obtained. To this was added 1 ml of water and the pH value of the resulting solution was adjusted to 7.8 with sodium hydrogencarbonate, and the solution was purified with HP-20 resin (methanol/H2O=1/4) to obtain 110 mg of the above-entitled compound.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:20][CH3:21])[C:6]1=[O:22])=[O:4].[NH2:23][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)=[O:28]>>[Br:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH2:20][CH3:21])[C:6]3=[O:22])=[O:4])[CH:39]=[CH:38][CH:37]=2)=[O:28])=[CH:31][CH:32]=1
Reactant: Nc1cccc(C(=O)Nc2ccc(Br)cc2)c1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3ccc(Br)cc3)c2)c2cc(C(C)=O)ccc21

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-(4-bromo-phenyl)-benzamide. mp 117-120° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].C(Cl)Cl.[C:8]([Si:12](Cl)([CH3:14])[CH3:13])([CH3:11])([CH3:10])[CH3:9]>C(OC(=O)C)C>[Br:1][CH2:2][CH2:3][O:4][Si:12]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:14])[CH3:13]
Reactant: OCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 1.8 %

Procedure:
To a solution of 2-bromoethanol (3.4 mL, 48.34 mmol) in dry DCM (25 mL) imidazole (9.86 g, 143 mmol) and tert-butylchlorodimethylsilane (10.9 gm, 72.52 mmol) were added at 0° C. The reaction mixture was stirred at r.t. for 24 h. After completion of reaction, as confirmed by TLC, the reaction mixture was diluted with ethylacetate (350 mL) and washed with water (4×20 mL). The organic layer was dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 0.2:9.8 Ethyl acetate:Pet. Ether) to afford title compound (204 mg, 77.5%) as liquid.