Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[CH:19][CH2:20][OH:21])=[CH:10]1)C1C=CC=CC=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:11]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[CH:19][CH:20]=[O:21])=[CH:10]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCC=Cc1cn(OCc2ccccc2)c2ccccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=CC=Cc1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
A mixture of 5 g (19 mmol) of 1-benzyloxy-3-(3-hydroxy-1 propen-1-yl) indole and 25 g of activated manganese dioxide in 500 ml of dichloromethane was stirred at room temperature for three hours and filtered through Celite®. The manganese compound was washed thoroughly with a mixture of dichloromethane and ethyl acetate until the Celite® layer was colorless. The combined filtrate and washing were concentrated on rotary evaporator and the residue was purified on a dry column (25% ethyl acetate in hexane) to give 2.3 g of 3-(1-benzylindol-3-yl)acrolein.
Reaction SMILES: [SH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].N12CCCN=C1CCCCC2>C(#N)C>[CH3:17][O:16][C:12](=[O:15])[CH2:13][CH2:14][S:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: C=CC(=O)OC
Reactant: O=C(O)c1cccc(CS)c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCSCc1cccc(C(=O)O)c1

Procedure:
Into a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(mercaptomethyl)benzoic acid (500 mg, 2.97 mmol, 1.00 equiv) in acetonitrile (10.0 mL), then methyl acrylate (10.0 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.0 g, 6.57 mmol, 2.00 equiv) were added in series. The resulting solution was heated to reflux overnight. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (0˜1:6). This resulted in 220 mg (28%) of 3-((3-methoxy-3-oxopropylthio)methyl)benzoic acid as a light-red oil.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]([O:9][CH:10]([O:20][CH2:21][CH3:22])[CH2:11][O:12][CH:13]([CH:17]1[CH2:19][CH2:18]1)[CH2:14]C=C)[CH3:8]>ClCCl>[CH:17]1([CH:13]([O:12][CH2:11][CH:10]([O:9][CH2:7][CH3:8])[O:20][CH2:21][CH3:22])[CH2:14]/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4])[CH2:19][CH2:18]1
Reactant: C=CC(=O)OC
Reactant: C=CCC(OCC(OCC)OCC)C1CC1
Solvent: ClCCl
Product: CCOC(COC(C/C=C/C(=O)OC)C1CC1)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl prop-2-enoate (69.5 mL, 767 mmol) and benzylidene[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro(tricyclohexylphosphine)ruthenium (Grubbs catalyst, second generation) (1.30 g, 1.53 mmol) in dichloromethane (102 mL) was added to a solution of [1-(2,2-diethoxyethoxyl)but-3-en-1-yl]cyclopropane (C15) (7.00 g, 30.7 mmol) in dichloromethane (102 mL), and the reaction mixture was stirred at room temperature for 3 hours. After removal of solvent under reduced pressure, the residue was mixed with diethyl ether and filtered through Celite. The filter pad was washed with additional diethyl ether, and the combined filtrates were concentrated in vacuo. Purification using silica gel chromatography (Gradient: 0% to 30% ethyl acetate in heptane) afforded the product as an oil. Yield: 6.0 g, 21 mmol, 68%. 1H NMR (400 MHz, CDCl3) δ 7.04 (dt, J=15.7, 7.4 Hz, 1H), 5.85-5.91 (m, 1H), 4.59 (dd, J=5.4, 5.2 Hz, 1H), 3.64-3.74 (m, 6H), 3.52-3.61 (m, 2H), 3.44 (dd, J=10.3, 5.5 Hz, 1H), 2.76 (dt, J=8.5, 5.9 Hz, 1H), 2.51 (ddd, J=7.3, 5.9, 1.4 Hz, 2H), 1.19-1.24 (m, 6H), 0.78-0.89 (m, 1H), 0.57-0.66 (m, 1H), 0.37-0.52 (m, 2H), 0.03-0.11 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[CH2:15]([O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][N:21]=1)=[O:19])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:15]([O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:22][N:21]=1)=[O:19])[CH3:16]
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: CCOC(=O)c1ccc(O)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)cn1
Yield: 43.2 %

Procedure:
To a stirred solution of (5-methyl-3-phenyl-4-isoxazolyl)methanol (570 mg, 3.01 mmol) and 5-hydroxy-pyridine-2-carboxylic acid ethyl ester (655 mg, 3.92 mmol) in THF (15 mL) under argon was added triphenylphosphine (1.03 g, 3.93 mmol). Diethyl azodicarboxylate (1.71 mL of a 40% solution in toluene, 682 mg, 3.92 mmol) was added dropwise. After 20 h the reaction mixture was concentrated in vacuo, water was added, and the reaction mixture extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated then purified by chromatography (silica, 10 to 60% ethyl actetate in heptane) afforded the title compound (440 mg, 43%) as a pink oil. MS: m/e=339.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([NH:1][C:2]1[S:3][C:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[N:6]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cc1sc(N)nc1-c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)Cc1sc(NC(C)=O)nc1-c1ccc(Cl)cc1

Procedure:
A mixture of 13.4 grams of ethyl (2amino-4-p-chlorophenyl-thiazol-5-yl)acetate and 10.2 grams of acetic anhydride in 50 c.c. of anhydrous pyridine is refluxed for 1/2 an hour. The solution is poured on ice. The precipitated solid is filtered off, washed several times with H2O, and recrystallised from 80% alcohol, m.p. 187°-88°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[CH:16]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)CCc1ccc(Br)cc1
Reactant: Br[Mg]C1CCCCC1
Solvent: CCOCC
Product: O=C(CCc1ccc(Br)cc1)C1CCCCC1
Reaction time: 1.25 h

Procedure:
To a solution of 25.02 g 3-(4-Bromophenyl)-N-methoxy-N-methylpropanamide from Step A above in 500 mL anhydrous ether cooled in an ice bath was added 115 mL 2 M cyclohexylmagnesium bromide in ether over 30 minutes. The cooling bath was removed after finishing addition. After 75 minutes, an additional 30 mL 2 M cyclohexylmagnesium bromide in ether was added. The reaction mixture was stirred for 40 minutes and poured into a mixture containing 500 mL ether, 500 mL cold water, 200 mL saturated brine, and 175 mL 2 N HCl. The layers were separated. The aqueous layer was extracted with 4×75 mL ether. The combined ether solution was washed with 200 mL 1:1 5% NaHCO3 and saturated brine followed by 200 mL saturated brine, dried over anhydrous Na2SO4, and evaporated to give a crude product. It was purified on silica gel using 20-100% EtOAc in hexanes and re-purified using 5-10% EtOAc in hexanes to give the title compound as yellow oil. 1H NMR (CDCl3, 500 MHz) δ 7.39˜7.42 (m, 2H), 7.06˜7.09 (m, 2H), 2.84˜2.87 (m, 2H), 2.74˜2.78 (m, 2H), 2.32 (tt, J=3.3 & 11.3 Hz, 1H), 1.76˜1.84 (m, 4H), 1.65˜1.70 (m, 1H), 1.15˜1.36 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([NH:12]C(=O)OC(C)(C)C)[CH:6]2[OH:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:12][CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])[CH:6]1[OH:11]
Reactant: CC(C)(C)OC(=O)NC1Cc2c(F)cccc2C1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1Cc2c(F)cccc2C1O
Yield: 65.3 %

Procedure:
To a solution of 1,1-dimethylethyl (4-fluoro-1-hydroxy-2,3-dihydro-1H-inden-2-yl)carbamate (0.30 g, 1.1 mmol) in CH2Cl2 (10 mL) was added TFA (1 mL), and the solution was heated to reflux. The solution was immediately cooled and concentrated in vacuo. The residue was taken up in MeOH and treated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8. The product was filtered and concentrated in vacuo to give 0.12 g (64% yield) of 2-amino-4-fluoro-2,3-dihydro-1H-inden-1-ol, which was used without further purification for the subsequent reductive amination.
Reaction SMILES: C([O-])(O)=[O:2].[Na+].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[C:20]1[C:29]([F:30])=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:31]=[C:32]([CH3:48])[N:33]([C@H:34]4[CH2:39][CH2:38][N:37]([CH:40](CC=O)[C:41]([O-:43])=O)[CH2:36][C@@H:35]4[F:47])[C:23]=3[C:22]=2[CH:21]=1.CO.C(Cl)Cl>CO>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[C:20]1[C:29]([F:30])=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:31]=[C:32]([CH3:48])[N:33]([C@H:34]4[CH2:39][CH2:38][N:37]([C:40](=[O:2])[CH2:41][OH:43])[CH2:36][C@@H:35]4[F:47])[C:23]=3[C:22]=2[CH:21]=1
Reactant: O=C([O-])O
Reactant: Cc1nc2cnc3cc(F)c(-c4ccc(Oc5ncccn5)cc4Cl)cc3c2n1[C@H]1CCN(C(CC=O)C(=O)[O-])C[C@@H]1F
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2cnc3cc(F)c(-c4ccc(Oc5ncccn5)cc4Cl)cc3c2n1[C@H]1CCN(C(=O)CO)C[C@@H]1F
Reaction time: 24 h
Yield: 81.7 %

Procedure:
NaHCO3 (11 g, 0.1309 mol) was added to a stirred solution of 2-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-oxoethylacetate (8 g, 0.013 mol) in MeOH (300 mL) at RT and stirred for 24 h. The reaction was monitored by TLC (5% MeOH/DCM), after completion of reaction, the reaction mixture was filtered and wand washed with MeOH (100 mL). The filtrate was concentrated to remove methanol and the residue was dissolved in DCM (200 mL) and washed with water, brine solution, dried over sodium sulphate and evaporated under vacuum. The residue was purified by column chromatography on silica gel (0-4% MeOH/DCM) to afford the 1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone (6.0 g, 81% yield). Obtained solid was recrystallized in EtOH (alternatively in MeOH) 1HNMR (CDCl3, 400 MHz): δ 9.33 (s, 1H), 8.65-8.64 (d, 2H), 8.08-8.05 (d, 1H), 8.00-7.85 (m, 1H), 7.51-7.30 (m, 2H), 7.30-7.28 (dd, 1H), 7.15-7.13 (m, 1H), 5.65-5.25 (m, 1H), 4.96-4.75 (m, 1H), 4.35-4.15 (m, 2H), 3.92-3.74 (m, 2H), 3.35-3.15 (m, 1H), 3.05-2.85 (m, 2H), 2.80 (s, 3H), 2.45-2.15 (m, 2H); LCMS: 100%, m/z=565.1 (M+1); HPLC (Method-3): 99.80%, Chiral HPLC: 99.48%, rt=20.38 min., Column. AG/CHIRALPAK AD-H/03. Free Form
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:18][CH:17]([NH:19][C:20](=[O:39])[CH2:21][NH:22][C:23](=[O:38])[C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=2[C:34]([F:37])([F:36])[F:35])[CH2:16]1)=O)(C)(C)C>>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:21][NH:22][C:23](=[O:38])[C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=2[C:34]([F:35])([F:37])[F:36])=[O:39])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cc(C(F)(F)F)ccc2C(F)(F)F)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1C(F)(F)F)NC1CNC1

Procedure:
The title compound was prepared as colorless oil from TFA de-protection of 3-[2-(2,5-bis-trifluoromethyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butylester using the procedure described in Step D of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)=[O:4].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Br:15])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Reaction time: 64 h

Procedure:
All of the 4-methoxycarbonyl-2-nitrotoluene obtained as described above was dissolved in carbon tetrachloride. Approximately 14.2 g (0.082 mole) of N-bromosuccinimide was added to the carbon tetrachloride solution. The resulting solution was heated to reflux temperature and stirred for approximately 64 hours. The solution was cooled and the succinimide was removed by vacuum filtration. The remaining solution was concentrated on a rotary evaporator using water aspirator vacuum. The synthesis produced 24 g of 4-methoxycarbonyl-2-nitrobenzyl bromide. The cholate ester of this product was then prepared as described for the preparation of the esters in Section B. The O,O,O-triacetyl derivative was also prepared as described in Section F.
Reaction SMILES: C[Si]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(C=C)C=C.[C:13]([Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])#[CH:14]>C1(C)C=CC=CC=1>[CH:22]([Si:15]([C:13]#[C:14][SiH:15]([CH3:16])[CH:13]=[CH:14][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])([CH3:24])[CH3:23]
Reactant: C=C[Si](C)(C=C)c1ccccc1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)[Si](C#C[SiH](C)C=Cc1ccccc1)(C(C)C)C(C)C

Procedure:
As in reaction conditions of Example XIX Step 1, to 2.12 mL of toluene, the 0.02 g carbonylchlorohydridebis(tricyclohexylphosphine)ruthenium(II) was added, and the reaction was carried out between 2.88 g methylphenyldivinylsilane and 0.50 g ethynyltri(isopropyl)silane. Raw [(tri(isopropyl)silyl)ethynyl]methylphenylvinylsilane was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:23][CH2:22][C:12]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]3=[O:21])[C:10]=2[CH:11]=1.N1C2C(=CC=CC=2)[C@@]2(C3C(=C[C:37]4[O:42][CH2:41][CH2:40][O:39][C:38]=4[CH:43]=3)OC2)C1=O>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:23][CH2:22][C:12]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:43][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:37])[C:13]3=[O:21])[C:10]=2[CH:11]=1
Reactant: COCCOc1ccc2c(c1)C1(CO2)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Product: COCCOCCN1C(=O)C2(COc3ccc(OCCOC)cc32)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9.70 and making non-critical variations using 5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 5-(2-methoxyethoxy)-1′-[2-(2-methoxyethoxy)ethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (80%) as a colorless oil: 1H NMR (300 MHz, DMSO-d6) δ7.31-7.27 (m, 1H), 7.15-7.10 (m, 1H), 7.06-6.99 (m, 2H), 6.63-6.58 (m, 1H), 6.56-6.53 (m, 1H), 6.42-6.36 (m, 1H), 4.81 (ABq, 2H), 4.11-4.02 (m, 2H), 3.83-3.76 (m, 2H), 3.75-3.70 (m, 2H), 3.69-3.54 (m, 4H), 3.52-3.45 (m, 2H), 3.43 (s, 3H), 3.33 (s, 3H); MS (ES+) m/z 414.1 (M+1).
Reaction SMILES: [I:1][CH:2]=[CH:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]([Mg]Br)#[CH:12].[Cl-].[NH4+]>O1CCCC1>[C:11]([C:4]([OH:10])([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:3]=[CH:2][I:1])#[CH:12]
Reactant: CCCCCC(=O)C=CI
Reactant: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)(C=CI)CCCCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 7.9 g. of 1-iodo-1-octen-3-one in 30 ml. of tetrahydrofuran is added dropwise over 10 minutes to an ice-cooled solution of ethynyl magnesium bromide (prepared from 21 ml. of 3M methyl magnesium bromide in ether and excess acetylene) in 170 ml. of tetrahydrofuran. After stirring at 0° for 1 hour under nitrogen, the mixture is added to ammonium chloride solution and extracted with ether. The extract is washed, dried, evaporated and the residue distilled to obtain the title product, 5.05 g., b.p. 55°-65°/.005 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:28]([C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[Cl:20])(=[O:30])=[O:29])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1Cl
Reaction time: 0.08 h
Yield: 47.5 %

Procedure:
To a round-bottom flask, was added 5-bromo-2-chloropyridin-3-amine (0.2 g, 1.0 mmol, Asymchem Laboratories, Morrisville, N.C.) in THF (10 mL). To this solution, sodium bis(trimethylsilyl)amide (1M in THF, 3 mL, 3 mmol, Aldrich, St. Louis, Mo.) was added and the mixture was stirred for 5 minutes. Then 2-chloro-4-fluorobenzene-1-sulfonyl chloride (0.7 g, 3 mmol, Aldrich, St. Louis, Mo.) was added to the mixture and the suspension was stirred at 25° C. for 15 h. The mixture was diluted with H2O. The organic layer was collected by extracting the water with DCM (3×). The combined organic was dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (1 to 30% EtOAc/CH2Cl2) gave N-(5-bromo-2-chloropyridin-3-yl)-2-chloro-4-fluorobenzenesulfonamide (0.190 g, 49% yield) as a tan oil. MS (ESI positive ion) m/z: 401 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:24]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[N:10]([C:35](=[O:37])[CH3:36])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC)cc1)C(C(=O)OC)NCC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC)cc1)C(C(=O)OC)N(C(C)=O)CC2
Reaction time: 8 h

Procedure:
To a mixture of the compound obtained in Example 12 (1.70 g) and pyridine (20 ml) is added acetic anhydride (5 ml), and the mixture is stirred overnight. The solvent is distilled off, and to the resulting residue is added chloroform, and the mixture is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/ethanol=10:1) to give methyl 2-n-butyl-5-acetyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-4,5,6,7-tetrahydroimidazo[4,5-c] pyridine-4-carboxylate (0.47 g) as an oil. NMR (CDCl3) δ: 0.88 (3H, t), 2.21 (3H, s), 3.46 (3H, s), 3.64 (3H, s), 5.33 (2H, ABq)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]3[C:19]=2[CH3:20])=[CH:4][CH:3]=1.[CH2:21]([N:23]=[C:24]=[S:25])[CH3:22]>C(O)C>[CH3:20][C:19]1[N:13]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]2=[N:11][C:10]=1[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:24]([NH:23][CH2:21][CH3:22])=[S:25])=[CH:3][CH:4]=1
Reactant: CCN=C=S
Reactant: Cc1ccn2c(C)c(CCc3ccc(N)cc3)nc2c1
Solvent: CCO
Product: CCNC(=S)Nc1ccc(CCc2nc3cc(C)ccn3c2C)cc1

Procedure:
A mixture of 2-[2-(4-aminophenyl)ethyl]-3,7-dimethylimidazo[1,2-a]pyridine (2.2 g) and ethyl isothiocyanate (0.8 ml) in ethanol (20 ml) was refluxed for 1.5 hours. The solvent was evaporated and the residue was triturated with diethyl ether. The precipitate was collected by filtration and dried to give 3,7-dimethyl-2-[2-{4-(3-ethylthioureido)phenyl}ethyl]imidazo[1,2-a]pyridine (2.42 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][NH:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]3[CH2:31][C:32]3[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=3)[O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O[C@H]1CN[C@@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)C1
Reactant: CCOC(=O)COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(CN2C[C@H](O)C[C@@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a mixture of (2R, 4R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidin-4-ol (229 mg) and potassium carbonate (155 mg) in DMF (5 mL) was added ethyl 3-(bromomethyl)phenoxyacetate (245 mg) at 5° C. and stirred at the same temperature for 30 minutes then at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc, 1:2) to give ethyl 3-{[(2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidin-1-yl]methyl}phenoxyacetate (359.7 mg).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH:14]([NH:16][CH:17]1[C:41](=[O:42])[N:19]2[CH:20]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH:21]([OH:24])[CH2:22][S:23][C@H:18]12)=[O:15].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[CH:14]([NH:16][CH:17]1[C:41](=[O:42])[N:19]2[C:20]([C:25]([O:27][CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:26])=[C:21]([OH:24])[CH2:22][S:23][C@H:18]12)=[O:15]
Reactant: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
A solution of trifluoroacetic anhydride (2.12 ml) in methylene chloride (5 ml) was added dropwise to a solution of dimethyl sulfoxide (1.56 g) in methylene chloride (10 ml) at -50° C. The mixture was stirred at -50° C. for 10 minutes. To the mixture was added a solution of benzhydryl 7-formamido-3-hydroxycepham-4-carboxylate (4.12 g) in methylene chloride (10 ml) and dimethyl sulfoxide (1 ml). The mixture was stirred at -50° C. for 30 minutes and triethylamine (4 ml) was added dropwise thereto at -50° C. The reaction mixture was allowed to warm up to ambient temperature, poured into ice-water and extracted with methylene chloride. The extract was washed three times with water, dried over magnesium sulfate and filtered, and the filtrate was evaporated in vacuo The residue was triturated with diisopropyl ether to give benzhydryl 7-formamido-3-hydroxy-3-cephem-4-carboxylate (3.42 g) as powder.