Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[Si:16]([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:17][Si:16]([CH3:19])([CH3:18])[O:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][N:11]([Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][Si:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: C[Si](C)(C)Cl
Reactant: O=C1NCCN1c1ccc(O)c(O)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Oc1ccc(N2CCN([Si](C)(C)C)C2=O)cc1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.4 g (17.5 mmol) of 1-(3,4-dihydroxyphenyl)-2-imidazolidinone in 10 ml of ethyl acetate was added 7.6 g (70 mmol) of chlorotrimethylsilane, and subsequently 7.0 g (70 mmol) of triethylamine. After stirring overnight at room temperature, the precipitate was filtered off under nitrogen and the filtrate evaporated to dryness in vacuo; yield: 7.14 g.
Reaction SMILES: [CH2:1]([CH:3]([NH2:6])[CH2:4][CH3:5])[CH3:2].[Cl:7][C:8]1[N:9]=[C:10]([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C:19]2=O)=[O:16])[NH:11][C:12]=1[CH2:13][CH3:14].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1.CO>[Cl:7][C:8]1[N:9]=[C:10]([C:15]([NH:17][C@@H:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C@H:19]2[NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:16])[NH:11][C:12]=1[CH2:13][CH3:14]
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Reactant: CCC(N)CC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(CC)CC)nc1Cl
Temperature: 50 °C
Reaction time: 15 h
Yield: 7 %

Procedure:
1-Ethylpropylamine (124 μL, 1.06 mmol) was added to a solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (197 mg, 0.531 mmol) in tetrahydrofuran (4 mL), and the mixture was heated under reflux at 50° C. for four hours. Methanol (3 mL) was added to the reaction solution. Sodium cyanoborohydride (100 mg, 1.59 mmol) and acetic acid (304 μL, 5.31 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v) to obtain 49 mg of the cis isomer of the title compound (21%) as a pale yellow oily substance and 16 mg of the trans isomer of the title compound (7%) as a pale yellow oily substance.
Reaction SMILES: [F:1][CH:2]([CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:18]=[CH2:19])[CH2:3][CH2:4][CH:5]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6]([OH:8])=O.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[C:55]([O:59][C:60](=[O:64])[C@H:61]([CH3:63])[NH2:62])([CH3:58])([CH3:57])[CH3:56].CN1CCOCC1>ClCCl>[C:55]([O:59][C:60](=[O:64])[C@H:61]([CH3:63])[NH:62][C:6](=[O:8])[C@H:5]([CH2:4][CH2:3][CH:2]([F:1])[CH:17]([CH:18]=[CH2:19])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:58])([CH3:57])[CH3:56]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: C=CC(NC(=O)OC(C)(C)C)C(F)CCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: C=CC(NC(=O)OC(C)(C)C)C(F)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound 5-fluoro-2,6-di-tert-butoxycarbonylamino-7-octenoic acid, 26, prepared as in Example II above (636 mg, 1.63 mmoles), 1-hydroxybenzotriazole monohydrate (250 mg) and dry dichloromethane (30 mL) are stirred at room temperature for 15 minutes. After cooling to 0° C., dicyclohexylcarbodiimide (370 mg) is added and stirring is continued for 1 hour at 0° C. and for 2 hours at room temperature. After cooling to 0° C. again, L-alanine-tert-butylester, hydrochloride (296 mg) is added, followed by N-methylmorpholine (330 mg). The mixture is stirred for 1 hour at 0° C., then at room temperature overnight. Filtration, washing (NaHCO3, NaHSO4, water), drying (Na2SO4) and evaporation yields an oil. This oil is dissolved in dichloromethane, filtered and evaporated. This last procedure is repeated several times to completely remove the DCU, leaving the title compound as an oil, 800 mg (95%).
Reaction SMILES: C1(CC(CC(=O)NCC)C(N(C(=O)[C@H](CC2N=CNC=2)N)N)=O)C2C(=CC=CC=2)C=CC=1.Cl.N(OCCC(C)C)=O.[C:42]1([CH2:52][CH:53]([CH2:69][C:70](=[O:74])[NH:71][CH2:72][CH3:73])[C:54]([NH:56][C@H:57]([C:64]([N:66]=[N+]=[N-])=[O:65])[CH2:58][C:59]2[N:63]=[CH:62][NH:61][CH:60]=2)=[O:55])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1.[N-]=[N+]=[N-].Cl.N[C@@H:80]([CH2:87][CH:88]([CH3:90])[CH3:89])[CH:81]([OH:86])[C:82]([O:84][CH3:85])=[O:83]>CN(C)C=O.C(N(CC)CC)C>[C:42]1([CH2:52][CH:53]([CH2:69][C:70](=[O:74])[NH:71][CH2:72][CH3:73])[C:54]([NH:56][C@H:57]([C:64]([NH:66][C@@H:80]([CH2:87][CH:88]([CH3:90])[CH3:89])[CH:81]([OH:86])[C:82]([O:84][CH3:85])=[O:83])=[O:65])[CH2:58][C:59]2[N:63]=[CH:62][NH:61][CH:60]=2)=[O:55])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)C(O)[C@@H](N)CC(C)C
Reactant: CCNC(=O)CC(Cc1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N=[N+]=[N-]
Agent: CC(C)CCON=O
Agent: CCNC(=O)CC(Cc1cccc2ccccc12)C(=O)N(N)C(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)CC(Cc1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC(C)C)C(O)C(=O)OC
Reaction time: 16 h

Procedure:
To a suspension of 207 mg of N-[2-(1-naphthylmethyl)-3-(ethylcarbamoyl)propionyl]-L-histidine hydrazide in 3 ml of dry N,N-dimethylformamide were added successively 0.30 ml of a dry 5.1N-hydrogen chloride in N,N-dimethylformamide solution and 0.076 ml of isoamyl nitrite at -20° C. with stirring. After disappearance of hydrazide compound, the reaction mixture was cooled to -30° C. and neutralized with 0.22 ml of triethylamine to prepare a solution of N-[2-(1-naphthylmethyl)-3-(ethylcarbamoyl)propionyl]-L-histidine azide. The cold azide solution was added dropwise to a solution of 100 mg of methyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride and 0.66 ml of triethylamine in 2 ml of dry N,N-dimethylformamide under ice-cooling, and the mixture was stirred for 16 hours. The reaction mixture was evaporated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent chloroform/methanol=15/1, Rf1 =0.43) to obtain 77 mg of methyl (2RS, 3S)-3-{N-[2-(1-naphthylmethyl)-3-(ethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][N:8]([C:16](=[O:33])[CH:17]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(C)(C)C.Cl.[NH2:36][OH:37].C(N(CC)CC)C>C(O)(C)C>[CH:27]1([CH:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH:36][OH:37])=[CH:23][CH:24]=2)[C:16]([N:8]([CH2:7][C:6]([OH:34])=[O:5])[CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)CN(CC1CCCCC1)C(=O)C(Cc1ccc(C#N)cc1)C1CCCCC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: N=C(NO)c1ccc(CC(C(=O)N(CC(=O)O)CC2CCCCC2)C2CCCCC2)cc1

Procedure:
{[3-(4-Cyano-phenyl)-2-(R,S)-cyclohexyl-propionyl]-cyclohexylmethyl-amino}-acetic acid tert-butyl ester (2.0 g, 4.29 mmol), hydroxylamine hydrochloride (0.89 g, 12.87 mmol) and triethylamine (1.3 g, 12.87 mmol) were stirred in isopropanol (80 ml) at room temperature for 24 hours. After evaporation, the residue was treated with potassium hydrogen sulfate solution and extracted with dichloromethane. The organic layer was dried and evaporated. Yield: 1.52 g (80%), MS m/z: 444.3 (M+H)+.
Reaction SMILES: [Br-].[C:2]([CH2:7][S+](C)C)([O:4][CH2:5][CH3:6])=[O:3].N12CCCN=C1CCCCC2.[C:22]1(=[O:27])[CH2:26][CH2:25][CH:24]=[CH:23]1.Cl.[Cl-].[Na+]>C1(C)C=CC=CC=1>[O:27]=[C:22]1[CH2:26][CH2:25][C@@H:24]2[C@H:23]1[C@H:7]2[C:2]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: O=C1C=CCC1
Reactant: CCOC(=O)C[S+](C)C
Agent: Cl
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1[C@@H]2CCC(=O)[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A suspension of carboethoxymethyl dimethylsulfonium bromide (45.5 g, 198.6 mmol) in toluene (350 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (30.2 g, 198.4 mmol). The resulting mixture was stirred at room temperature. After one hour, the reaction mixture was treated with 2-cyclopenten-1-one (19.57 g, 238.4 mmol). After an additional 18 hours, the reaction mixture was added to a 1 N hydrochloric acid/sodium chloride solution. The resulting mixture was extracted with diethyl ether. The combined ether extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica-gel chromatography, eluting with a linear gradient of 10% ethyl acetate/hexanes to 50% ethyl acetate/hexanes, to give 22.81 g (68%) of the title compound. Melting point: 36-38° C.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]=2[N:4]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>ClC(Cl)C>[CH2:15]([O:14][C:12]([C:11]1[C:5]2[N:4]=[C:3]([CH2:2][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[NH:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)=[O:13])[CH3:16]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cccc2[nH]c(CCl)nc12
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cccc2[nH]c(CN3CCOCC3)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.3 %

Procedure:
To a solution of ethyl 2-chloromethyl-1H-benzimidazole-4-carboxylate (250 mg) in dichloroethane (2.5 ml) was added morpholine (183 mg) under ice bath cooling and the reaction mixture was stirred at ambient temperature for 15 hours. To the reaction mixture was added morpholine (91 mg) and stirred at 80° C. for 6 hours. After the reaction mixture was concentrated in vacuo, the residue was diluted with chloroform and saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and washed with brine. The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (methanol:chloroform=1:9) to give ethyl-2-morpholinomethyl-1H-benzimidazole-4-carboxylate (219 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21]N1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCCCCC1C[CH2:72][N:71]([C:74]([O:76][CH2:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)=[O:75])[CH2:70][CH2:69]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:24][CH2:23][CH:22]1[CH2:21][CH2:72][N:71]([C:74]([O:76][CH2:77][C:78]2[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=2)=[O:75])[CH2:70][CH2:69]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCCCBr)CC1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 4-(6-bromohexyl)-1-piperidinecarboxylate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:23]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2B(O)O)[CH:27]=[CH:26][CH:25]=[N:24]1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1ccccc1-n1cccn1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccccc4-n4cccn4)c3)cnc2c1F
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-(pyrazol-1-yl)benzeneboronic acid were coupled in the same way as in Example 30 to give 2-{8-fluoro-3-[2-fluoro-2′-(pyrazol-1-yl)biphenyl-5-yl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (5 mg, 4%): m/z (ES+) 431 [MH+].
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH:15]([CH:18]=O)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH:15]([CH:18]=[CH2:1])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a suspension consisting of methyl triphenylphosphonium bromide (4.76 g, 13.3 mmol) and THF (20 mL) at 0° C. was added n-butyl lithium (1.6 M solution in hexanes, 8.3 mL). The resulting orange solution was stirred at 0° C. for 5 min. A solution consisting of 3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.50 g, 12.5 mmol) and THF (15 mL) was then added via cannula. The reaction mixture was stirred at 0° C. and was warmed to rt over 2.5 h. The reaction mixture was then cooled to 0° C., quenched with sat. NH4Cl, and extracted with Et2O. The organic layer was combined, dried (MgSO4) and concentrated. The crude residue was suspended in hot hexanes and filtered. The filtrate was concentrated and purified (FCC) to give the title compound (1.7 g, 70%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][C:44]=1[Cl:45])[NH:41][CH:40]=[C:39]2[S:46]([OH:49])(=[O:48])=[O:47].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO>[Cl:45][C:44]1[CH:43]=[C:42]2[C:38]([C:39]([S:46]([OH:49])(=[O:48])=[O:47])=[CH:40][NH:41]2)=[CH:37][C:36]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CCOCC2)cc1
Reactant: O=S(=O)(O)c1c[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCOCC4)cc3)cc12
Temperature: 100 °C
Yield: 3.3 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indole (300 mg, 1.30 mmol) and sulfur trioxide pyridine complex (622 mg, 3.91 mmol) in pyridine (2 mL) was sealed in a pressure tube and heated to 100° C. for 48 hours. The reaction mixture was concentrated in vacuo to provide 5-bromo-6-chloro-1H-indole-3-sulfonic acid as a pyridinium salt, which was used directly in the next step without further purification. A mixture of 4-(4-bromophenyl)tetrahydropyran (77.0 mg, 0.32 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (121 mg, 0.35 mmol), potassium acetate (95.0 mg, 0.97 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.0 mg, 0.016 mmol) in 1,4-dioxane (1 mL) was sealed and heated to 100° C. for 1 hour. To the mixture was added the above freshly prepared 5-bromo-6-chloro-1H-indole-3-sulfonic acid (100 mg, 0.32 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.0 mg, 0.016 mmol), 2N aqueous potassium carbonate solution (0.65 mL, 1.30 mmol) and EtOH (5 mL). The reaction mixture was sealed and heated to 130° C. for 1 hour. The reaction mixture was diluted with water (10 mL), acidified to pH 2 and washed with EtOAc (10 mL). The aqueous layer was concentrated in vacuo and purified by reversed phase HPLC (Column: Waters Sunfire C18 19×100, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); HOLD at 100.0% H2O/0.0% MeCN for 1.0 min. 100.0% H2O/0.0% MeCN linear to 5.0% H2O/95.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 mL/min.) to provide the title compound (4.1 mg, 3%). MS (ES−) 390.0 (M−H)+. Retention time=2.12 minutes (Waters Atlantis dC18 4.6×50, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:8]=[C:9]([NH2:21])[C:10]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:12]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[C:22](Cl)(=O)[C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:26]1[N:13]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10]2[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:5])=[O:6])=[CH:8][C:9]=2[N:21]=1)([CH3:25])([CH3:24])[CH3:22]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)S(=O)(=O)c1ccc(NCC2CCOCC2)c(N)c1
Product: CC(C)S(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step C of Example 17 from 4-(isopropylsulfonyl)-N′-(tetrahydro-2H-pyran-4-ylmethyl)benzene-1,2-diamine (Step B) and pivaloyl chloride.
Reaction SMILES: ClCCl.[C:4]([O:8][C:9]([C:11]([N:16]1[CH:19]([S:20]C=O)[CH:18]([NH:23][C:24](=[O:33])[CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17]1=[O:34])=[C:12]([OH:15])[CH2:13]Br)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)(=O)C>[O:26]([CH2:25][C:24]([NH:23][CH:18]1[C:17](=[O:34])[N:16]2[C:11]([C:9]([O:8][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:10])=[C:12]([OH:15])[CH2:13][S:20][C@H:19]12)=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)C(=C(O)CBr)N1C(=O)C(NC(=O)COc2ccccc2)C1SC=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1=C(O)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 391 mg. of mercuric acetate in 15 ml. of dichloromethane containing 15 ml. of acetic acid was added in one portion 435 mg. of 1-(1-tert.-butyloxycarbonyl-2-hydroxy-3-bromo-1-propenyl)-3-phenoxyacetamido-4-formylthio-azetidin-2-one. The reaction mixture was stirred at room temperature for 5 minutes, and then hydrogen sulfide gas was bubbled into the reaction mixture for 1 minute. The reaction mixture was filtered through a filter aid and charcoal. The filtrate was evaporated to dryness under reduced pressure to provide tert.-butyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([O:7]C)=[O:6].CO.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C2SCCNc3c2c(-c2ccccn2)nn3C)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.7 %

Procedure:
A mixture of methyl 3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzoate (0.060 g, 0.15 mmol, Example #E.1), methanol (5 mL), THF (5 mL) and 2 M aqueous NaOH (3 mL) was stirred at rt for about 18 h. Subsequently, 1 M aqueous HCl (7 mL) was added and the volatiles were removed in vacuo. The residue was treated with water (20 mL) and then extracted with ethyl acetate (2×70 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (Table 2, Method a) to give 3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzoic acid (0.016 g, 0.04 mmol, 27%) as an off white solid: LC-MS (Table 1, Method a) Rt=3.0 min; m/z 401 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.58-2.75 (2H, m) 3.06 (1H, t, J=11.8 Hz) 3.68-3.76 (1H, m) 3.77 (3H, s) 5.82 (1H, d) 7.03 (1H, s) 7.14-7.18 (1H, m) 7.42 (1H, d, J=8.0 Hz) 7.66-7.72 (2H, m) 7.79 (1H, d, J=8.0 Hz) 7.89 (1H, d, J=1.7 Hz) 8.43-8.48 (1H, m).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][C:8]=1[CH3:9].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>>[CH:19]1([CH2:18][O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])=[N:7][C:8]=2[CH3:9])[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: Cc1nc(NC(=O)C(C)(C)C)ccc1CO
Product: Cc1nc(NC(=O)C(C)(C)C)ccc1COCC1CC1

Procedure:
This material was prepared in analogy to example 86 step A] from N-(5-Hydroxymethyl-6-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.445 g) and bromomethyl cyclopropane (0.275 g) as a light yellow oil (0.357g). MS (ESI): 277.2 (MH+).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:8]([O:16][CH3:17])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([Br:6])[C:8]=1[O:16][CH3:17]
Reactant: COc1c(Br)cccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Br)c1OC
Temperature: 25 °C

Procedure:
5.0 mL of sulfuric acid (H2SO4) was slowly added to a solution of 5.0 g of 3-bromo-2-methoxy-benzoic acid 4 in 100 mL of methanol (MeOH). The resulting solution was heated to reflux overnight. The solution was cooled to room temperature and quenched with sodium bicarbonate to pH 7. The aqueous layer was extracted several times with ethyl acetate. The combined organic extracts were washed with brine and dried over sodium sulphate. The resulting mixture was filtered. The solvents were evaporated under reduced pressure to afford 5.3 g of 3-bromo-2-methoxy-benzoic acid methyl ester 5.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.N1C=CC=CC=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[S:28]([O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 10 h

Procedure:
To a suspension of (R)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (400 mg, 1.858 mmol) and pyridine (1.10 ml, 13.60 mmol) in tetrahydrofuran (5 ml) was added p-toluenesulfonyl chloride (425 mg, 2.230 mmol) and stirred for 10 hr. To the reaction was added citric acid (4 g) and water (10 mL) and extracted with ethyl acetate (3×10 mL). The organics were combined, dried (MgSO4), filtered, and concentrated. The residue was purified by Analogix® Intelliflash280 ™ (SiO2, 0-40% ethyl acetate in hexanes). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.13-1.21 (m, 1 H) 1.23-1.31 (m, 1 H) 1.37 (s, 9 H) 1.46-1.55 (m, 1 H) 1.59-1.74 (m, 2 H) 2.43 (s, 3 H) 2.68-2.83 (m, 1 H) 3.28-3.32 (m, 1H), 3.67-3.73 (m, 2 H) 3.89 (d, J=6.10 Hz, 2 H) 7.49 (m, 2 H) 7.76-7.81 (m, 2 H); MS (DCI) m/z 387 (M+NH4)+.