Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([OH:18])([CH2:16][CH3:17])[C:4]#[C:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1)[OH:7])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([C:3]([OH:18])([CH2:16][CH3:17])[C:4]#[C:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1)=[O:7])[CH3:2]
Reactant: CCC(O)(C#CC(O)c1ccc(SC)cc1)CC
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(O)(C#CC(=O)c1ccc(SC)cc1)CC
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.5 %

Procedure:
To a stirred suspension of celite (20 g) and 4-ethyl-1-{4-(methylthio)phenyl}-2-hexyn-1,4-diol (11 g) in 300 ml dichloromethane, was added 25 g of pyridinium dichromate at 0° C. Then the reaction mixture was stirred for 12 hours at room temperature. The insoluble and metallic substances were removed by filtration through Florisil. The filtrate was extracted with dilute aqueous HCl and dichloromethane (150 ml×3). The organic layer was then washed with brine and dried over anhydrous magnesium sulfate. The organic layer was concentrated in vacuo and the resulting crude product was recrystallized from 5:1 hexane and ethylacetate to yield 7.8 g of 4-ethyl-4-hydroxy-1-{4-(methylthio)phenyl}-2-hexyn-1-one as a low-melting solid. mp: 49-50° C. NMR: δ1.12 (t, J=7.5 Hz, 6H), 1.83 (q, J=7.5 Hz, 4H), 2.15 (br s, 1H), 2.54 (s, 3H), 7.28 (d, J=8.7 Hz, 2H), 8.02 (d, J=8.7 Hz, 2H). IR (cm−1): 3432, 2970, 2208, 1636, 1588, 1285, 1095.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:10][CH2:11][N:12]([CH2:38][CH2:39][NH2:40])[CH2:13][CH2:14][N:15]([CH2:35][CH2:36][NH2:37])[CH2:16][CH2:17][N:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:50]([OH:52])[CH3:51]>C(#N)C.C(=O)([O-])[O-].[K+].[K+]>[C:45]([O:44][C:42]([CH2:41][N:9]([CH2:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][CH2:11][N:12]([CH2:38][CH2:39][N:40]([CH2:19][CH2:20][OH:21])[CH2:8][CH2:6][OH:7])[CH2:13][CH2:14][N:15]([CH2:35][CH2:36][N:37]([CH2:2][CH2:1][OH:5])[CH2:51][CH2:50][OH:52])[CH2:16][CH2:17][N:18]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(O)Br
Reactant: CC(C)(C)OC(=O)CN(CCN(CCN)CCN(CCN)CCN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(CCN(CCN(CCO)CCO)CCN(CCN(CCO)CCO)CCN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C

Procedure:
N,N,N"',N"'-tetra(t-butyloxycarbonylmethyl)-N',N"-di(2-aminoethyl)-triethylenetetramine is dissolved in acetonitrile with an excess of potassium carbonate, and a solution of bromoethanol (3 equivalents) in acetonitrile is added dropwise with stirring; the solution is then heated to reflux for 18 hours. The reaction mixture is then filtered and the filtrate evaporated to dryness to give N,N,N"',N"'-tetra(t-butyloxycarbonylmethyl)-N',N"-di(N,N-bis(2-hydroxyethyl)-2-aminoethyl)-triethylenetetramine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[CH:25][CH:24]=[CH:23]4)=[CH:16][C:15]=2[CH2:30][NH:31][CH2:32][CH3:33])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:35]([N:42]=[C:43]=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[CH:25][CH:24]=[CH:23]4)=[CH:16][C:15]=2[CH2:30][N:31]([CH2:32][CH3:33])[C:43]([NH:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:44])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(-c2ccc3ncccc3c2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc4ncccc4c3)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-quinolin-6-yl-biphenyl-3-yl)-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [CH2:1]([CH:3]([C:9](O)([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC)C(O)(c1ccccc1)c1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CC)=C(c1ccccc1)c1ccc(OC)cc1
Yield: 107.9 %

Procedure:
7.3 g (0.02 mol) of ethyl 2-ethyl-3-hydroxy-3-(p-methoxyphenyl)-3-phenylpropionate were dehydrated in 150 ml of chloroform by using trifluoroacetic acid as catalyst (see example 10) to give 6.7 g (93%) of product, which was a mixture of E- and Z-isomers.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[N:5]=[C:6](Cl)[C:7]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1>CO.[Pd]>[CH3:17][O:16][CH:3]([O:2][CH3:1])[C:4]1[N:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1
Reactant: COC(OC)c1nc(Cl)c2c(n1)NC(=O)CC2
Agent: [Pd]
Solvent: CO
Product: COC(OC)c1ncc2c(n1)NC(=O)CC2
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To crude 2-[bis(methyloxy)methyl]-4-chloro-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (prepared from 1.43 g 4-chloro-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2-carbaldehyde) dissolved in MeOH (50 mL) was added 10% Pd/C (wet) (0.15 g). The solution was stirred under an atmosphere of H2 (balloon) overnight. The Pd/C was filtered off and the solution concentrated under vacuum. The crude residue was purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired product as a white solid (0.873 g, 58% over 2 steps).
Reaction SMILES: Cl.C(N)(=N)C1C=CC=CC=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=3)[CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1>>[C:15]1([C:18]2[N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([Br:30])=[CH:28][CH:29]=3)[CH:21]=[CH:20][N:19]=2)[CH:14]=[CH:13][CH:12]=[CH:17][CH:16]=1
Reactant: Brc1ccc(-c2ccnc(-c3ccc(Br)cc3)n2)cc1
Agent: Cl
Agent: N=C(N)c1ccccc1
Product: Brc1ccc(-c2ccnc(-c3ccccc3)n2)cc1
Yield: 72 %

Procedure:
Benzamidine hydrochloride (4.7 g, 0.03 mole) and 1-dimethylamino-3-dimethylimonio-1-(4-bromophenyl)-1-propene perchlorate are allowed to react as described above in Example 4 for the preparation of 2,4-Bis(4-bromophenyl)-pyrimidine. After work-up and recrystallization from CHCl3 :ethyl ether (1:3), 7.2 g (72%) of a white crystalline solid is obtained which melted at 107°-08° C. IR(KBr) 2925, 1597, 1562, 1540, 1427 cm-1. 1H-NMR: (CDCl3) 8.65 (d, 1H, j=5.3 Hz), 8.55-8.52 (m, 2H), 8.02 (d, 2H, j=8.3 Hz), 7.6 (d, 2H, j=8.8 Hz), 7.5-7.46 (m, 3H), 7.44 (d, 1H, j=5.3 Hz). 13C-NMR (CDCl3): 164.6, 162.5, 157.9, 137.6, 135.7, 132.1, 130.8, 128.6, 128.5, 128.2, 125.6, 114.1. MS m/e: 311 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.S(O)(O)(=O)=O.Cl[C:25]1[NH:26][CH2:27][CH2:28][N:29]=1>CC(O)C.C(OCC)(=O)C>[NH:29]1[CH2:28][CH2:27][N:26]=[C:25]1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: ClC1=NCCN1
Reactant: Nc1ccc(CCC(=O)c2ccc(F)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccc(NC2=NCCN2)cc1)c1ccc(F)cc1
Yield: 67.4 %

Procedure:
A mixture of 3-(4-aminophenyl)-1-(4-fluorophenyl)propan-1-one (1.17 g, 4.81 mmol) and 2-chloro-4,5-dihydro-1H-imidazole sulfate (1.95 g, 9.62 mmol) (prepared according to the procedure described in Trani, A and Bellasio, E., J. Het. Chem. 1974, 11, 257) in 2-propanol (20 mL) was heated under reflux for 15 minutes. The reaction mixture was cooled and diluted with ethyl acetate (150 mL) and washed with 5% sodium hydroxide solution, water, and brine. The organic layer was separated and dried with potassium carbonate, and evaporated in vacuo. Purification by silica gel chromatography, eluting with 10% methanol/dichloromethane containing 1% ammonium hydroxide, gave 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-fluorophenyl)propan-1-one as an oil (1.01 g, 76.5%). The oil was converted to the hydrochloride salt, m.p. 190.2-190.8° C. Analysis for C18H19CIFN3O.0.2H20: Calcd.: C, 61.52; H, 5.56, N, 11.96. Found: C, 61.40; H, 5.47; N, 11.97.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5](Cl)=[O:6])[CH3:3].[C:8]([O:12][C:13](=[O:27])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1)([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.O>C(Cl)Cl>[C:8]([O:12][C:13](=[O:27])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:5](=[O:6])[CH2:4][N:2]([CH3:3])[CH3:1])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CN(C)CC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CCNCC2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)N1CCC(c2ccc(NC(=O)OC(C)(C)C)cc2)CC1
Reaction time: 6 h

Procedure:
Dimethylamino-acetyl chloride (0.14 g, 0.86 mmol) and (4-piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.20 g, 0.72 mmol) were combined in CH2Cl2 (5 mL) and triethylamine (0.21 g, 2.2 mmol) was added. After 6 h, water (5 mL) was added. The reaction mixture was extracted with CH2Cl2 (3×5 mL) and the combined organic extracts were dried (MgSO4) and concentrated. The compound was found to be unstable on silica and therefore carried on without further purification. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.04 (s, 1H), 7.52 (d, 2H, J=8.5 Hz), 7.16 (d, 2H, J=8.5 Hz), 3.06 (s 2H), 2.76-2.82(m, 2H), 2.59-2.65 (m, 1H), 2.37 (s, 6H), 1.78-1.81 (m, 2H), 1.54-1.64 (m, 2H), 1.48 (s, 9H), 1.30 (br s, 2H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:24][C:23]([CH2:25][NH:26][CH2:27][CH:28]([OH:36])[CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[N:22][N:21]=2)[CH:3]=1.[CH3:37][O:38][C:39]1[C:44]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][N:40]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[OH:36][CH:28]([CH2:29][N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1)[CH2:27][NH:26][CH2:25][C:23]1[O:24][C:20]([C:4]2[CH:3]=[C:2]([C:42]3[CH:43]=[C:44]([NH:45][S:46]([CH3:49])(=[O:47])=[O:48])[C:39]([O:38][CH3:37])=[N:40][CH:41]=3)[CH:10]=[C:9]3[C:5]=2[CH:6]=[N:7][NH:8]3)=[N:21][N:22]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CNCC(O)CN4CCOCC4)o3)cc(Br)cc21
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(-c3nnc(CNCC(O)CN4CCOCC4)o3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
1-[({5-[6-Bromo-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3,4-oxadiazol-2-yl}methyl)amino]-3-(4-morpholinyl)-2-propanol (100 mg, 0.346 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (81 mg, 0.247 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (25.35 mg, 0.0345 mmol) and potassium phosphate tribasic (110.5 mg, 0.5195 mmol) were added to a mixture of 1,4-dioxane (2.5 ml) and water (0.25 ml). The reaction mixture was heated under microwave irradiation at 80° C. for 30 mins and then 100° C. for 10 mins. The mixture was then passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated by a hydrophobic frit and the solvent again removed under a stream of nitrogen. The protected compound was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml) and stirred at room temperature for 1 h. The mixture was neutralised with addition of 2M HCl, dissolved in DMSO, filtered through a filter tube and purified by high pH MDAP (Method E). The appropriate fractions and waste were evaporated to dryness in vacuo. The residue was dissolved in 1:1 DMSO/water and purified by preparative HPLC using the following method:
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C:9]([OH:20])([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>C(O)CCC>[OH:20][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCC(O)(c2ccc(Cl)c(Cl)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: OC1(c2ccc(Cl)c(Cl)c2)CCNCC1
Yield: 90 %

Procedure:
A mixture of 64.2 g of 1-ethoxycarbonyl-4-hydroxy-4-(3,4-dichlorophenyl)piperidine (X-1) and a solution of 72.4 g of KOH in 700 ml of nBuOH is refluxed for 2 hours and evaporated. The reaction mixture is concentrated under reduced pressure and extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated. The resulting crystalline residue is recrystallized from ethyl acetate to prepare 44.7 g (Yield: 90.0%) of the compound (II-1). mp. 144.5°-146.0° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:19]1([C:25]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:26]2[CH:30]=[C:29]([CH2:31]Cl)[N:28]=[CH:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:31][C:29]1[N:28]=[CH:27][N:26]([C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:30]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOP([O-])OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
To a solution of diethylphosphite (4.30 g, 31.2 mmol) in dry tetrahydrofuran (hereinafter abbreviated to THF) (10 ml) was added 1M THF solution of lithium bis-(trimethylsilyl)amide (31.2 ml, 31.2 mmol) dropwise over 1 hour at −72° C. under argon flow, followed by adding dropwise (1-triphenylmethylimidazol-4-yl)methyl chloride (9.30 g, 26.0 mmol) in THF (80 ml) over 30 minutes. The reaction mixture was stirred for 15 minutes at the same temperature, and then was heated to room temperature and stirred for additional 3 hours at room temperature. After the reaction was quenched by addition of saturated aqueous ammonium chloride (150 ml), the THF was removed and the residue was extracted four times with ethyl acetate (100 ml). The organic layers were dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained crude pale yellow solid product was purified by chromatography on silica gel column using methanol-ethyl acetate (1:20) to give diethyl(1-triphenylmethylimidazol-4-yl)methylphosphonate (10.30 g, 86%) as a white powder. This powder was recrystallized from a mixture of ethyl acetate and hexane to provide the titled compound as white small needles (m.p. 141-144° C.).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15](/[CH:18]=[CH:19]\[CH2:20][O:21][CH3:22])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[C:31]([O:34][CH:35](Br)[CH3:36])(=[O:33])[CH3:32]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O:25][CH:35]([O:34][C:31](=[O:33])[CH3:32])[CH3:36])=[O:24])=[C:15](/[CH:18]=[CH:19]\[CH2:20][O:21][CH3:22])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OC(C)Br
Reactant: COC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Product: COC/C=C\C1=C(C(=O)OC(C)OC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Yield: 43 %

Procedure:
Esterification of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-3-methoxy-1-propenyl]-3-cephem-4-carboxylic acid (300 mg, 0.66 mmole) with 1-bromoethyl acetate in a similar manner to that described in Example 10 gave the title compound (154 mg, 43%). Mp. 102°-105° C. (dec.). Estimated purity 95% (by HPLC, 1:1 CH3CN-pH 7 phosphate buffer).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH:25]([NH:34][C:35]([CH:37]1[N:41]2[C:42](=[O:61])[CH:43]([NH:48][C:49]([C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[CH:52]=3)=[O:50])[CH2:44][CH:45]=[CH:46][CH2:47][CH:40]2[CH2:39][CH2:38]1)=[O:36])[CH2:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:23][CH:24]1[CH:25]([NH:34][C:35]([CH:37]2[N:41]3[C:42](=[O:61])[CH:43]([NH:48][C:49]([C:51]4[CH:60]=[CH:59][C:58]5[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=5)[CH:52]=4)=[O:50])[CH2:44][CH:45]=[CH:46][CH2:47][CH:40]3[CH2:39][CH2:38]2)=[O:36])[CH2:26][C:27](=[O:28])[N:29]1[S:30]([CH3:33])(=[O:31])=[O:32]
Reactant: CS(=O)(=O)NC(=O)CC(CO)NC(=O)C1CCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)N1C(=O)CC(NC(=O)C2CCC3CC=CCC(NC(=O)c4ccc5ccccc5c4)C(=O)N32)C1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
Dess-Martin reagent (90 mg, 0.21 mmol) is added to an ice cold solution of 6-[(Naphthalene-2-carbonyl)-amino]-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid (1-hydroxymethyl-3-methanesulfonylamino-3-oxo-propyl)-amide (48 mg, 0.09 mmol) in CH2Cl2 (5 mL). The solution is stirred at 0 C. for 2 h and treated with saturated NaHCO3. The resulting solution is extracted with EtOAc and the combined organic extracts are washed with brine, dried (Na2SO4), filtered, and concentrated. The crude residue obtained is purified by flash chromatography on silica gel (CH2Cl2/MeOH) to yield 27 mg of product as a mixture of diastereomers. MS (ESI) 555 (M+1).
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2]>Cl.O1CCOCC1>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[N:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@]1(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.8 %

Procedure:
tert-Butyl [(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]carbamate (290 mg, 0.60 mmol) was dissolved in a 4.0 M solution of HCl in 1,4-dioxane (10 mL). After being stirred at room temperature for 1 h, the mixture was concentrated to give 270 mg of desired product. MS calculated for C18H26F3N5O: (M+H) 386; found 386.1.
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:33][CH:32]3[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]([CH2:30][CH2:31]3)[CH2:28]2)[CH:9]=1.C(O)(=O)C.[Br:56]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[CH3:49][Si:46]([CH3:47])([CH3:48])[CH2:45][CH2:44][O:43][CH2:42][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:50])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:33][CH:32]3[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]([CH2:30][CH2:31]3)[CH2:28]2)[C:9]=1[Br:56]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(C(C)(C)O)nc4)c3n1)C2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1nc3c(-c4ccc(C(C)(C)O)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C2
Yield: 99.5 %

Procedure:
tert-butyl 3-{7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-3-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-5-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate (0.500 g, 0.676 mmol) was dissolved in acetic acid (3.5 mL, 62 mmol) and N-bromosuccinimide (144.2 mg, 0.8105 mmol) was added in a single portion, and the reaction was monitored by HPLC. The reaction was complete in less than 10 min and the mixture was diluted with ethyl acetate and poured into a 1:1 mixture of saturated aq. sodium bicarbonate and aq. sodium thiosulfate (20%). The layers were separated and the organics washed several times with sodium bicarbonate solution then brine. The organics were dried with magnesium sulfate, filtered and concentrated to provide 550 mg of the desired material.
Reaction SMILES: [Cl:1][C:2]1C=CC(SCCl)=CC=1.[CH:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12].CC(C)([O-])C.[K+].C1CCCCC=1>CN(C=O)C.C(Cl)Cl>[Cl:1][CH2:2][N:13]([CH:11]=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=CNc1ccccc1
Reactant: ClCSc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: O=CN(CCl)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
4-Chloro-1-(chloromethylthio)benzene (21 mmol) was added to a mixture of formanilide (21 mmol) and potassium tert-butoxide (21 mmol) in DMF (200 ml). The mixture was stirred at 80° C. for 4 hours before the solvent was distilled off and the residue dissolved in ether and washed five times with water, and the dried (MgSO4) solution evaporated. Yield: 5.37 g (92%), m.p. 67° C. (Pet. ether/ether). The product (17.8 mmol) was dissolved in CH2Cl2 (100 ml) and SO2Cl2 (17.8 mmol) in CH2Cl2 (25 ml) was added with stirring at 5° C. for 30 minutes. The mixture was stirred for 15 minutes before cyclohexene (19.3 mmol) in CH2Cl2 (25 ml) was added. The mixture was evaporated and the residue washed with hexane and dried. The product was used in the Example 28 without further purification. 1H NMR (CDCl3,δ): 5.50 (s, --CH2 --), 7.34 (Ph), 8.33 (CHO).