Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:31]([O:35][C:36](=[O:56])[CH2:37][C@H:38]([NH:42][S:43]([C:46]1[C:51]([CH3:52])=[CH:50][C:49]([O:53][CH3:54])=[CH:48][C:47]=1[CH3:55])(=[O:45])=[O:44])[C:39](O)=[O:40])([CH3:34])([CH3:33])[CH3:32].[CH3:57][O:58][CH:59]([O:62][CH3:63])[CH2:60][NH2:61]>C(Cl)Cl>[CH3:57][O:58][CH:59]([O:62][CH3:63])[CH2:60][NH:61][C:39](=[O:40])[C@@H:38]([NH:42][S:43]([C:46]1[C:51]([CH3:52])=[CH:50][C:49]([O:53][CH3:54])=[CH:48][C:47]=1[CH3:55])(=[O:44])=[O:45])[CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:56]
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O)c(C)c1
Reactant: COC(CN)OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)NCC(OC)OC)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
Diisopropylethylamine (2.5 eq) followed by HOBT (1.0 eq) and EDCI (1.5 eq) was added to a solution of (S)-4-tert-butoxy-2-(4-methoxy-2,6-dimethylphenyl-sulfonamido)-4-oxobutyric acid (1.91 mmol, 1.0 eq) in DCM (10 ml/mmol) at 0° C. The resulting solution was stirred for 15 min at 25° C., cooled to 0° C. again and 2,2-dimethoxyethanamine (1.2 eq) was added. The reaction mixture was stirred for 16 h at 15° C. It was then diluted with DCM and extracted with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and finally saturated sodium chloride solution. The organic phase was dried (Na2SO4) and concentrated to low volume under vacuum. The crude product was processed by column chromatography. Yield: 70%
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[C:20]1([CH2:26][CH2:27][C:28](=O)[CH3:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH3:29][C:28]1([CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:6][C:1](=[O:7])[CH2:2][C:3](=[O:5])[O:4]1
Reactant: CC(=O)CCc1ccccc1
Reactant: O=C(O)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC1(CCc2ccccc2)OC(=O)CC(=O)O1
Reaction time: 0.33 h

Procedure:
To a solution of malonic acid (56.7 g, 0.55 mol) and acetic anhydride (73 ml), sulfuric acid (2 ml) was added dropwise at 5°-10° C. and stirring was continued for 20 min at the same temperature. To this mixture, 4-phenyl-2-butanone (105 g, 0.7 mol) was added dropwise at 15°-20° C. and stirring was continued for 15 h at the same temperature. The reaction mixture was taken up into H2O, extracted with chloroform, then the organic extract was washed with H2O, dried over anhydrous MgSO4 and evaporated. The resultant solid was recrystallized from aqueous acetone to give the title compound as a white amorphous solid; yield: 68.0 g; mp. 63.0°-65.0° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[CH3:25][C:26]([C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32])([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:31]([C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[C:26]([CH3:28])([CH3:27])[CH3:25])=[O:32]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: CC(C)(C)c1ccccc1C(=O)O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccccc1C(C)(C)C

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[[2-(1,1-dimethylethyl)phenyl]carbonyl]-L-phenylalanine methyl ester was prepared from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2-(1,1-dimethylethyl)benzoic acid using the general procedure described in example 3. HR MS: Obs. mass. 527.1523. Calcd. mass. 527.1573 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[CH2:9]2)=[CH:4][C:3]=1Br.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:26]1(B(O)O)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[CH2:9]2)=[CH:4][C:3]=1[C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: CN1C(=O)CC(c2ccc(N)c(Br)c2)CC1=O
Reactant: OB(O)C1=CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CN1C(=O)CC(c2ccc(N)c(C3=CCCCC3)c2)CC1=O
Temperature: 80 °C
Yield: 99.9 %

Procedure:
A suspension of 265 mg (0.892 mmol) of 4-(4-amino-3-bromo-phenyl)-1-methyl-piperidine-2,6-dione (as prepared in the previous step) in toluene (15 mL) and dioxane (15 mL) was treated with 379 mg (1.78 mmol) of K3PO4, 146 mg (1.16 mmol) of cyclohex-1-enylboronic acid, and 125 mg (0.357 mmol) of 2-(dicyclohexylphosphino)-biphenyl. The mixture was degassed via sonication, placed under Ar, treated with 20.0 mg (0.00892 mmol) of Pd(OAc)2, and heated to 80° C. for 2.5 h. The mixture was diluted with EtOAc (70 mL) and washed with water (2×50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25-50% EtOAc-hexane afforded 266 mg (100%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C18H22N2O2, 299.2 (M+H). found 299.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[O:9])[S:6][CH:7]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1)[CH3:2]
Reactant: CCc1csc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1csc(CO)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 74.3 %

Procedure:
To a stirred solution of 4-ethyl thiophene-2-carbaldehyde (2.48 g, 17.7 mmol) in methanol (10 ml) at 0° C. is added sodium borohydride (707 mg, 18.7 mmol) in one portion. The resultant solution is allowed to warm to ambient and stirred at room temperature for 40 minutes. Reaction is concentrated in vacuo, quenched with saturated aqueous ammonium chloride solution (100 ml) and extracted with chloroform (100 ml). The organics are dried over magnesium sulphate, filtered and concentrated to give a light brown oil, which is purified by flash chromatography on silica gel to give (4-ethyl-thiophen-2-yl)methanol as a clear oil (1.87 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[N:24]=[N:25][N:26]([C:28]([CH3:36])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:29])[N:27]=2)=[CH:13][CH:12]=1)=O.O.[OH-].[Na+]>C1COCC1>[CH3:36][C:28]([N:26]1[N:25]=[N:24][C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:9][OH:8])=[CH:16][CH:15]=2)=[N:27]1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:29]
Reactant: COC(=O)c1ccc(-c2ccccc2-c2nnn(C(C)(C)c3ccccc3)n2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(CO)cc2)n1
Temperature: 0 °C
Yield: 99.5 %

Procedure:
A solution of lithium aluminum hydride (1.9 L, 1 M in THF) was cooled to -30° C. and 2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-carboxylic acid methyl ester (0.848 kg, 2.13 mol), prepared as in Example 3, in 3.5 L of THF was added at a rate such that the reaction temperature remained below -10° C. The mixture was allowed to warm to 0° C. and 77 mL of water, 77 mL of 15% sodium hydroxide and 230 mL of water were sequentially added. The mixture was filtered and the filter cake washed with 3×500 mL of THF. The filtrate was concentrated, then 4 L of hexanes were added and a crystalline product was obtained. The product was isolated by filtration and the filter cake was washed with hexanes. Drying gave 2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]-biphenyl-4-methanol (0.788 kg, 2.12 mol), m.p. 117°-120° C.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11])=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:20]1([C:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:4]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11])=[N:1][N:2]=[N:3]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N#CCCCCc1nnn[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCCCCc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
A solution of 1H-tetrazole-5-pentanenitrile (30 g, 198 mmol) in a mixture of methylene chloride (200 mL) and triethylamine (30 mL, 218 mmol) was stirred as trityl chloride (61 g, 218 mmol) was added. After 16 h, the reaction was treated with an aqueous solution of sodium bicarbonate and extracted with methylene chloride. The combined organic layers were dried and concentrated. The residue was dissolved in ether and hexane was added. The resulting solid was isolated by filtration to give 1-(triphenylmethyl)-1H-tetrazole-5-pentanenitrile as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)#[N:2].C(OC(C)(C)C)=O>>[NH2:24][C:23]1[C:3]([C:1]#[N:2])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCCC(COc2cccc([N+](=O)[O-])c2C#N)C1
Agent: CC(C)(C)OC=O
Product: CC(C)(C)OC(=O)N1CCCC(COc2cccc(N)c2C#N)C1
Yield: 100 %

Procedure:
Prepared as in example 254b from tert-butyl 3-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (Example 262e) in 100% yield as an oil. MS 232 [M+H-Boc]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][CH2:10]Br.[Br:12][C:13]1[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[CH:15][C:14]=1[OH:21]>CN(C=O)C>[Br:12][C:13]1[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[CH:15][C:14]=1[O:21][CH2:10][CH2:9][O:8][CH3:7]
Reactant: CCc1ccc(O)c(Br)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(OCCOC)c(Br)c1
Reaction time: 20 h
Yield: 89.3 %

Procedure:
Potassium carbonate (8.25 g, 60 mol) followed by 2-bromoethyl methyl ether (1.87 mL, 20 mmol) were added to a solution of 2-bromo-4-ethyl-phenol (4 g, 20 mmol, from step 1 of Example B(98)) in DMF (25 mL). The mixture was stirred for 20 hours and then partitioned between 1N HCl and EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude yellow oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes) to give the desired product (4.63 g, 90%). 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J=7.6 Hz, 3H), 2.57 (q, J=7.6 Hz, 2H), 3.48 (s, 3H), 3.79 (t, J=5.1 Hz, 2H), 4.15 (t, J=4.8 Hz, 2H), 0.6.85 (d, J=8.3 Hz, 1H), 7.06 (dd, J=8.3, 2.3 Hz, 1H), 7.37 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[N:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[CH2:19].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:1][C:2]1[CH:14]=[N:13][C:12]2[N:11]([CH2:19][CH2:18][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: C=Cc1ccncc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccncc2)CCN2CCCC12
Temperature: 100 °C
Yield: 23.2 %

Procedure:
9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene (250 mg, 1.10 mmol), 4-vinyl-pyridine (347 mg, 3.30 mmol), tetrabutyl ammonium bromide (355 mg, 1.10 mmol) were charged in a screw cap bottle and a 60% solution of sodium hydroxide (5 mL) was added and heated to 100° C. for 12 h. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with 25 mL of water and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (25 mL), dried over anhydrous sodium sulfate and concentrated. The resultant crude product was purified by reverse phase chromatography to obtain 85 mg of 9-methyl-6-(2-pyridin-4-yl-ethyl)-2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene as the formate salt (the product was a racemate which was purified by chiral prep HPLC to obtain product II-244a & product II-244b as the freebase). 1H NMR (CDCl3, freebase) δ (ppm): 8.45 (d, 2H), 8.17 (s, 1H), 7.56 (s, 1H), 6.91 (d, 2H), 4.5 (m, 1H), 4.42 (t, 1H), 4.35 (m, 1H), 3.26 (m, 2H), 3.16 (m, 5H), 2.81 (m, 1H), 2.45 (m, 1H), 2.41 (s, 3H), 2.1 (m, 2H), 1.9 (m, 1H). Separation by chiral HPLC provided enantiomers II-244a-b.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH2:8]([N:15]1[CH2:19][CH:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH:17]([NH2:28])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:8]([N:15]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C@H:17]([NH:28][C:5](=[O:7])[CH3:6])[CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
To a stirred solution of acetic anhydride (0.75 ml, 7.97 mmol) in THF (10 ml) was added a solution of rac-(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine (described herein above) (2.00 g, 6.22 mmol) in THF (10 ml) dropwise over 30 minutes. The reaction mixture was stirred one additional hour, concentrated under vacuo, taken up in EtOAc, washed with aq. NaHCO3. and then the organic phase was dried over Na2SO4 to afford the intermediate N-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-acetamide. To this intermediate in THF (10 ml) at 0° C., was added portion wise LiAlH4 (0.49 g, 12.83 mmol). Stirring was continued over night at 65° C.). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with aq. NaHCO3. The product was extracted several times with EtOAc, the organic phases were then dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 1.03 g (46%) of rac-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-amine as a colorless oil. ES-MS m/e: 349.10 (M+H+).
Reaction SMILES: [CH2:1]([C:3]12[CH2:10][CH2:9][C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([CH2:7][NH:8]1)[N:5]([CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19])[C:4]2=[O:28])[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([C:3]12[CH2:10][CH2:9][C:6]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH2:7][NH:8]1)[N:5]([CH2:17][C:18]([OH:20])=[O:19])[C:4]2=[O:28])[CH3:2]
Reactant: [H][H]
Reactant: CCC12CCC(c3ccccc3)(CN1)N(CC(=O)OCc1ccccc1)C2=O
Agent: [Pd]
Solvent: CO
Product: CCC12CCC(c3ccccc3)(CN1)N(CC(=O)O)C2=O

Procedure:
A mixture of benzyl (4-ethyl-3-oxo-1-phenyl-2,5-diazabicyclo[2.2.2]oct-2-yl)acetate from Step A (127 mg, 0.336 mmol) and 10% Pd/C (20 mg) in MeOH (5 mL) was stirred under a balloon of hydrogen. The reaction mixture was filtered and concentrated in vacuo to give the title compound. MS: m/z=289 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[C:6]([CH:17]=1)[CH2:7][N:8](C)[C:9](=O)OC(C)(C)C.Cl>C(OCC)(=O)C>[CH:21]([S:18]([C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:17][C:6]=1[CH2:7][NH:8][CH3:9])(=[O:19])=[O:20])([CH3:23])[CH3:22]
Reactant: CC(C)S(=O)(=O)c1ccc(N)cc1CN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCc1cc(N)ccc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 8A (1 g, 2.92 mmol) in ethyl acetate (10 ml) was added 4N HCl (29.2 ml, 117 mmol) and the mixture was stirred at r.t. for 4 h. Solvent was removed under reduced pressure to yield 8B (920 mg, 2.92 mmol, 100% yield) as a yellow solid. 1H NMR (500 MHz, methanol-d3) δ ppm 1.27 (d, J=6.60 Hz, 6H) 3.26-3.41 (m, 1H) 3.66 (s, 3H) 4.28 (s, 2H) 6.79-6.91 (m, 2H) 7.68 (d, J=8.80 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([CH:30]=1)[CH2:7][C@@H:8]1[CH2:14][N:13]([CH2:15][C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])[C:12](=O)[CH2:11][NH:10][C:9]1=[O:29].O1CCCC1.C1C=CC(OC2C=CC(P3(SP(C4C=CC(OC5C=CC=CC=5)=CC=4)(=S)S3)=[S:52])=CC=2)=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([CH:30]=1)[CH2:7][C@@H:8]1[CH2:14][N:13]([CH2:15][C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])[C:12](=[S:52])[CH2:11][NH:10][C:9]1=[O:29]
Reactant: S=P1(c2ccc(Oc3ccccc3)cc2)SP(=S)(c2ccc(Oc3ccccc3)cc2)S1
Reactant: COc1cc(OC)c(CN2C[C@@H](Cc3cc(Cl)ccc3OC)C(=O)NCC2=O)c(OC)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(OC)c(CN2C[C@@H](Cc3cc(Cl)ccc3OC)C(=O)NCC2=S)c(OC)c1
Reaction time: 3 h
Yield: 124.3 %

Procedure:
To the compound S140c described in WO 06-059801A, that is, (6R)-6-(5-chloro-2-methoxybenzyl)-1-(2,4,6-trimethoxybenzyl)-1,4-diazepane-2,5-dione (2.2 g) in a tetrahydrofuran (80 ml) solution, Belleau's reagent (1.5 g) was added under ice cooling, and the mixture was stirred at that temperature for 3 hours. The reaction solution was diluted with ethyl acetate, successively washed with saturated aqueous sodium hydrogencarbonate solution, water, and brine, dried over anhydrous sodium sulfate, then concentrated. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate=35/65 to 1/99) to obtain the title compound (1.69 g).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:24][NH:25][C:26]([NH2:28])=[O:27].CC([O-])=O.[Na+].O>CO>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[N:24][NH:25][C:26]([NH2:28])=[O:27])=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(N)=O
Reactant: O=Cc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)NN=Cc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Temperature: 100 °C
Reaction time: 64 h
Yield: 89.2 %

Procedure:
A mixture of 20.0 g of aldehyde from Example 17 Part A, 8.29 g of semicarbazide hydrochloride, 8.14 g of NaOAc and 150 mL of H2O was heated for 0.75 hours at 100° C. with occasional swirling. The heterogenous mixture was diluted with 150 mL of MeOH and allowed to stand at 25° C. for 64 hours. The solid was filtered and washed with H2O, refluxed with 500 mL of MeOH and filtered hot leaving 21.3 g of 4-(2-(2-phenyl-4-oxazolyl)ethoxy)benzaldehyde semicarbazone (89%, m.p. 221°-226° C.).
Reaction SMILES: C(O)(=O)C.O[C@@H]([C@H]1C(=O)N2C(C([O-])=O)=C(C3SC4=C(C(=O)CC)N=CN4C=3)[C@H](C)[C@H]12)C.[Na+].[Si]([O:40][CH2:41][CH2:42][N:43]([CH3:80])[S:44]([C:47]1[N:48]=[CH:49][N:50]2[CH:54]=[C:53]([C:55]3[C@H:56]([CH3:79])[C@@H:57]4[C@@H:74]([C@H:75]([OH:77])[CH3:76])[C:73](=[O:78])[N:58]4[C:59]=3[C:60]([O:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([N+:70]([O-:72])=[O:71])=[CH:66][CH:65]=3)=[O:61])[S:52][C:51]=12)(=[O:46])=[O:45])(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>C1COCC1>[OH:77][C@@H:75]([C@H:74]1[C:73](=[O:78])[N:58]2[C:59]([C:60]([O:62][CH2:63][C:64]3[CH:65]=[CH:66][C:67]([N+:70]([O-:72])=[O:71])=[CH:68][CH:69]=3)=[O:61])=[C:55]([C:53]3[S:52][C:51]4=[C:47]([S:44](=[O:45])(=[O:46])[N:43]([CH2:42][CH2:41][OH:40])[CH3:80])[N:48]=[CH:49][N:50]4[CH:54]=3)[C@H:56]([CH3:79])[C@H:57]12)[CH3:76]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(S(=O)(=O)N(C)CCO[Si](C)(C)C(C)(C)C)c4s3)[C@H](C)[C@H]12
Agent: CCC(=O)c1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(S(=O)(=O)N(C)CCO)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Acetic acid (0.36 ml) and 2.0 ml of a 1 M-tetra-n-butylammonium fluoride/THF solution were added under ice cooling to a solution of 273 mg, of 4-nitrobenzyl (1S,5R,6S)-2-[7-[N-(2-t-butyldimethylsilyloxyethyl)-N-methylsulfamoyl]imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 8 ml of THF. The mixture was stirred at room temperature for 6 hr. The reaction mixture was added to a dilute aqueous sodium hydrogencarbonate solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=10:1) to give 175 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-[N-(2-hydroxyethyl)-N-methyl-sulfamoyl]imidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]12[CH2:10][C:9](=[O:11])[CH2:8][CH:7]([CH2:12][CH2:13][C:14]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=3[CH3:21])[CH:6]1[CH2:5][CH2:4][C:3]2=[CH:22][CH2:23]O.C(Br)(Br)(Br)[Br:26]>>[CH3:1][C:2]12[CH2:10][C:9](=[O:11])[CH2:8][CH:7]([CH2:12][CH2:13][C:14]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=3[CH3:21])[CH:6]1[CH2:5][CH2:4][C:3]2=[CH:22][CH2:23][Br:26]
Reactant: Cc1ccc(O)cc1CCC1CC(=O)CC2(C)C(=CCO)CCC12
Reactant: BrC(Br)(Br)Br
Product: Cc1ccc(O)cc1CCC1CC(=O)CC2(C)C(=CCBr)CCC12

Procedure:
Following the general procedure of EXAMPLE 15 and making noncritical variations but starting with 3a-methyl-7-[2-(5-hydroxy-2-methylphenyl)-ethyl]-3-(2-hydroxyethylidene)-octahydro-5H-inden-5-one (EXAMPLE 13) and using carbon tetrabromide in place of carbon tetrachloride, the title compound is obtained, MS (EI) 392 and 390; NMR (CDCl3) 0.94, 1.61-2.1, 2.20, 2.3-2.8, 2.94, 4.0-4.2, 4.9, 5.4-5.5, 6.5-6.7 and 6.99 δ.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:15]([CH:16](Cl)[CH3:17])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:19])[N:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:5][C:6]1[C:15]([CH:16]([N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])[CH3:17])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:19])[N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(Cl)c1cc2c(Cl)cccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(c1cc2c(Cl)cccc2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 55 °C

Procedure:
Added thionyl chloride (301 μl, 4131 μmol). Obtained a clear colorless solution within minutes. Concentrated reaction mixture to dryness on the rotavap to obtain an oil, which was used without further purification. LC-MS (+esi, M+H+=260.0). Dissolved 2,5-dichloro-3-(1-chloroethyl)quinoline (215 mg, 825 μmol) in DMF (2 mL) and added phthalimide (127 mg, 866 μmol) and K2CO3 (228 mg, 1650 μmol). Submerged in oil bath and began heating to 55° C. After 10 min the temperature of the oil bath was raised to 80° C. After 30 more minutes the reaction mixture was partitioned between EtOAc:H2O. The organic layer was washed with water (3×), dried with sodium sulfate, filtered, and concentrated. The crude was solid was chromatographed on 12 g silica gel column with 0-20% EtOAc:Hex. The desired fractions were combined and concentrated to yield a white crystalline solid. 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.99 (d, J=7.04 Hz, 3 H) 5.93 (q, J=7.17 Hz, 1 H) 7.64-7.70 (m, 2 H) 7.71-7.76 (m, 2 H) 7.77-7.83 (m, 2 H) 7.88-7.93 (m, 1 H) 8.95 (s, 1 H). LC-MS (+esi, M+H+=371.0)