Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:29][CH:28]=2)[C:10]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44])C1C=CC=CC=1>CO.[Pd]>[CH3:25][N:23]([CH3:24])[C:22]([C:12]1[N:11]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][CH2:36][N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[CH:31][CH:32]=2)[C:10]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:9]([OH:8])[C:13]=1[OH:14])=[O:26]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OCCCN2CCOCC2)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OCCCN2CCOCC2)cc1
Yield: 27.1 %

Procedure:
A solution of ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-(3-morpholinopropoxy)phenyl)-1H-pyrrole-2-carboxylate (37) (105 mg, 0.16 mmol) in MeOH (4 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 25° C. under H2 (full H2 mode). The output was concentrated in vacuo, and a solid was collected by filtration after trituration with isohexane to afford ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-(3-morpholinopropoxy)phenyl)-1H-pyrrole-2-carboxylate (UL1-102) (20 mg, 25%) as a yellow solid: m/z 462 (M+H)+ (ES+), 460 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.58 (s, 1H), 8.44 (s, 1H), 7.05-6.99 (m, 2H), 6.86-6.82 (m, 2H), 4.03-3.95 (m, 4H), 3.61-3.53 (m, 4H), 2.82 (br s, 6H), 2.45-2.34 (m, 6H), 1.93-1.81 (m, 2H), 0.98 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24]([OH:26])=O)/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:42]1([NH:45][CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:44][CH2:43]1>CN(C=O)C.C(Cl)Cl>[CH:42]1([NH:45][CH:46]2[CH2:51][CH2:50][N:49]([C:24]([C:23]3[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=3/[CH:18]=[C:10]3\[C:11](=[O:17])[NH:12][C:13]4[C:9]\3=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:16]=[CH:15][CH:14]=4)=[O:26])[CH2:48][CH2:47]2)[CH2:44][CH2:43]1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Reactant: C1CC(NC2CC2)CCN1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC(NC3CC3)CC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (105 mg, 0.29 mmol), EDC (120 mg, 0.58 mmol), HOBt (40 mg, 0.3 mmol) in DMF (4 mL) was added TEA 90.15 mL) and cyclopropyl-piperidin-4-yl-amine. The mixture was stirred at rt for 20 hours. The reaction was diluted with DCM, washed with water, NaHCO3, dried and concentrated. The residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58]1[CH:63]=[CH:62][N:61]=[C:60]([C:64]2[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[NH:66][CH:65]=2)[CH:59]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([N:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58]1[CH:63]=[CH:62][N:61]=[C:60]([C:64]2[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[NH:66][CH:65]=2)[CH:59]=1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: c1ccc2c(-c3cc([C@@H]4CCCN4)ccn3)c[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ccnc(-c2c[nH]c3ccccc23)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of (S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (75 mg, 0.29 mmol), HOBt (46 mg, 0.33 mmol) and HBTU (127 mg, 0.33 mmol) in DMF (5 mL) is stirred at room temperature for 30 min. Then a solution of 3-((S)-4-pyrrolidin-2-yl-pyridine-2-yl)-1H-indole (15) in DMF (5 mL) is added, followed by diisopropylethylamine (198 mg, 1.50 mmol). After stirring at room temperature for 2 h, the reaction mixture is diluted with water and extracted with EtOAc. The combined organic layers are washed with water, sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by flash chromatography on silica gel (EtOAc/Hexane: 5%˜40%) to give ((S)-1-Cyclohexyl-2-{(S)-2-[2-(1H-indol-3-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester as a yellow solid (120 mg, 78%). Mass M/Z=503.34 [M+1]
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22]C([N+]([O-])=O)C4C=CC=CC=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].CO.O1CCCC1.C(O)(=O)C>[C].[Pd].O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=NOC2CCCCC2)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)[N+](=O)[O-])=CCS[C@H]23)cs1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: O=CNc1nc(C(=NOC2CCCCC2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 49.3 %

Procedure:
Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-cyclohexyloxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 2.0 g.), 10% palladium carbon (0.8 g.), methanol (8 ml.), tetrahydrofuran (20 ml.), acetic acid (0.14 ml.) and water (1.4 ml.) were treated in a similar manner to that of Example 15-(2) to give 7-[2-(2-formamidothiazol-4-yl)-2-cyclohexyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.77 g.).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:23])[C@H:10]2[NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=2)[C:7]=1[C:24]([O:26]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:23])[C@H:10]2[NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=2)[C:7]=1[C:24]([OH:26])=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3nc(C(=O)O)cs3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](Nc3nc(C(=O)O)cs3)[C@H]2SC1
Reaction time: 0.75 h
Yield: 73.2 %

Procedure:
A mixture of 300 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[(4-carboxy-2-thiazolyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 1 ml of trifluoroacetic acid, 0.25 ml of anisole and 3 ml of dichloromethane was allowed to stand for 45 minutes, then the solid was collected, washed with ether and petroleum ether and dried, giving 155 mg of the desired compound.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8].[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[S:23]>>[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([OH:17])[C:15]([C:22](=[S:23])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[CH3:19])=[CH:16][C:11]=2[CH:10]=1)=[O:8]
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Reactant: Cc1ccccc1C(=S)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)C1=Cc2cc(C(=S)c3ccccc3C)c(O)cc21

Procedure:
In a manner analogous to that described in Example 5, starting from 37.12 g of aluminium trichloride, 13.42 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester and 26.05 g of o-methylthiobenzoyl chloride there is obtained 4-(o-methylthiobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester in the form of a viscous yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCC
Product: C#Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 2(4-chlorophenyl)-1-trimethylsilylethyne Prepared in Stage 1 (30.90g:0.02 mole) in methanol was added potassium carbonate (0.276g:002 mole). The mixture was stirred at room temperature until starting material disappeared as monitored by gas liquid chromatography. After this time, solvent was removed in vacuo and the residue taken up in dichloromethane. The solution was dried and declourised over charcoal. Filtration, followed by removal of solvent gave a brown solid which was passed through silica in hexane. This gave pale yellow crystals (1.511g:55.3%)
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10](=[O:32])[NH:11][C@:12]([CH2:30][OH:31])([CH3:29])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:17][CH:16]=1)([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1.Cl>C(#N)C.CCOC(C)=O>[C:5]([O:9][C:10]([N:11]1[C:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:19][CH:20]=2)([CH3:29])[CH2:30][O:31][S@:1]1=[O:2])=[O:32])([CH3:8])([CH3:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCOc1ccc(CC[C@](C)(CO)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCOc1ccc(CCC2(C)CO[S@@](=O)N2C(=O)OC(C)(C)C)cc1
Temperature: -10 °C

Procedure:
A stirred solution of thionyl chloride (0.14 ml, 1.91 mMol) in acetonitril (10 ml) is cooled to −40° C. At this temperature, a solution of [(R)-3-(4-heptyloxy-phenyl)-1-hydroxymethyl-1-methyl-propyl]-carbamic acid tert-butyl ester (300 mg, 0.76 mMol) in acetonitril (5 ml), and pyridine (0.31 ml, 3.81 mMol) are added successively. The mixture is allowed to warm to −10° C. over 2.5 hours. The reaction mixture is then poured onto a biphasic mixture of AcOEt and HCl (aqueous, 1 M). The aqueous phase is extracted twice with AcOEt. The combined organic layers are washed with NaHCO3 (saturated aqueous solution), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography eluting with 5%→15% AcOEt in heptane gives the title compounds as colourless oils (2 diastereomers, dr=1:1).
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[CH3:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1>>[CH3:10][C:11]1[N:12]=[CH:13][N:14]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[N+:7]([O-:9])=[O:8])[CH:15]=1
Reactant: Cc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccsc1Cl
Product: Cc1cn(-c2sccc2[N+](=O)[O-])cn1
Yield: 49 %

Procedure:
4-methyl-1(3-nitrothiophen-2-yl)-1H-imidazole was prepared from 2-chloro-3-nitrothiophene and 4-methyl-1H-imidazole according to the procedure described in Example 9.7.1., above. Purification by flash column chromatography (silica, 40:60 ethyl acetate/hexane) gave the nitro intermediate (1.26 g, 49%). 1H-NMR (CDCl3) δ 7.67 (s, 1H), 7.59 (d, J=6.1 Hz, 1H), 7.19 (d, J=6.1 Hz, 1H), 6.89 (s, 1H), 2.27 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([N:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](=[O:18])[O:16][CH3:17])[CH:10]=[CH:9]2)(=[O:3])[CH3:2].CCN(CC)CC.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.O.[Br:48]Br>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:48][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([N:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](=[O:18])[O:16][CH3:17])[CH:10]=[CH:9]2)=[O:3]
Reactant: BrBr
Reactant: COC(=O)N(c1ccccc1)c1ccc2cccc(C(C)=O)c2n1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)N(c1ccccc1)c1ccc2cccc(C(=O)CBr)c2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of methyl (8-acetylquinolin-2-yl)(phenyl)carbamate (46b; 790 mg) was set stirring in DCM (2 mL) at 0° C. before adding Et3N (190 μl, 1.368 mmol), and TBSOTf (266 μl, 1.158 mmol) sequentially. An additional 3.0 equivalents of Et3N and TBSOTf were then added sequentially After 5 min., the mixture was diluted with sat. aq. NaHCO3, and extracted with DCM. The organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in THF (5 mL) before adding water (303 μL, 16.84 mmol) and Br2 (67.4 μl, 1.316 mmol, Sigma Aldrich). The resulting mixture was stirred at RT for 5 min, then diluted with sat. aq. NaHCO3 and extracted with DCM. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The brominated product was used without further purification in the subsequent transformation. m/z (ESI, +ve) 399.1 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:42])([CH2:21][CH2:22][C:23]([F:41])([F:40])[C:24]([F:39])([F:38])[C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=2)=[CH:10][CH:9]=1.[F:43][CH:44]([CH:57]([F:63])[CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH2:45]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:43][C@H:44]([C@@H:57]([F:63])[CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH2:45][O:20][C:17]1[CH:18]=[N:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:42])[CH2:21][CH2:22][C:23]([F:41])([F:40])[C:24]([F:38])([F:39])[C:25]([F:36])([F:37])[C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])=[CH:9][CH:10]=2)=[N:15][CH:16]=1
Reactant: C[Si](C)(CCCCOc1ccc(-c2ncc(O)cn2)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCC(F)C(F)COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCC[C@H](F)[C@@H](F)COc1cnc(-c2ccc(OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of compound 47 (0.162 g, 0.250 mmol), toluene-4-sulfonic acid 2,3-difluoro-octyl ester (0.080 g, 0.250 mmol) and cesium carbonate (0.098 g, 0.300 mmol) in DMF 5.0 ml) was stirred at room temperature for 24 h. The reaction mixture was washed with water and the organic layer extracted into ethyl acetate/hexane (3×20 ml, 1:1). The combine extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residues were purified by column chromatography [silica gel, hexane/ethyl acetate (9:1)] to yield a colorless solid, which was recrystallized from acetonitrile.
Reaction SMILES: ClC1C=CC=CC=1C(NC1NN=C(C(O)=O)C=1)=O.C([O:21][C:22]([C:24]1[C:28]([CH3:29])=[C:27]([NH:30][C:31](=[O:39])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])[N:26]([C:40]([CH3:43])([CH3:42])[CH3:41])[N:25]=1)=[O:23])C>>[C:40]([N:26]1[C:27]([NH:30][C:31](=[O:39])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])=[C:28]([CH3:29])[C:24]([C:22]([OH:23])=[O:21])=[N:25]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CCOC(=O)c1nn(C(C)(C)C)c(NC(=O)c2ccccc2Cl)c1C
Agent: O=C(O)c1cc(NC(=O)c2ccccc2Cl)[nH]n1
Product: Cc1c(C(=O)O)nn(C(C)(C)C)c1NC(=O)c1ccccc1Cl

Procedure:
The procedure described for compound 23 was employed using 1-tert-butyl-5-(2-chlorobenzoylamino)-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (49) to afford acid 52.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:21])[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:22]([OH:24])=[O:23].O.O.O.[S:29]1[CH2:33][CH2:32][CH2:31][CH:30]1O.[OH-].[Na+:36]>O.C(O)C>[Na+:36].[S:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[NH:21][CH:13]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:11]([NH:10][CH:7]1[C:8](=[O:9])[N:4]2[CH:5]1[S:6][C:2]([CH3:25])([CH3:1])[CH:3]2[C:22]([O-:24])=[O:23])=[O:12]
Reactant: OC1CCCS1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccc(O)cc3)C(=O)N2[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)SC2C(NC(=O)C(NC3CCCS3)c3ccc(O)cc3)C(=O)N2C1C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a stirred suspension of 6.7 g (0.016 mol) of amoxicillin trihydrate in 125 ml of distilled water was added in one portion 16 ml of 1 N aqueous sodium hydroxide solution. The amoxillin quickly dissolved and after two minutes 4.99 g (0.048 mol) of tetrahydrothiophene-2-ol dissolved in 10 ml of absolute ethanol was added. After stirring for two minutes at 25° C. the solution was quickly frozen and lyophilized for 19 hr to give 8.36 g of {2S-[2α, 5α, 6β(S*)]}-6-{[tetrahydro-2-thienylamino-(4-hydroxyphenyl)acetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid sodium salt as a slightly yellow pungent smelling powder.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35](=[O:40])[C:36]([F:39])([F:37])[F:38])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)C(F)(F)F)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NC(=O)C(F)(F)F)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-trifluoroacetylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]1([C:17]([N:19]=[C:20]=[O:21])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH:11]1([C:17]([NH:19][C:20]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][C:2]2=[O:10])=[O:21])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C=NC(=O)C1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)N1C(=O)Cc2ccccc21)C1CCCCC1
Temperature: 25 °C

Procedure:
To a stirred slurry of 20.0 g (0.15 mole) of 2-oxindole in 150 ml of toluene was added 29.6 g (0.19 mole) of cyclohexylcarbonyl isocyanate. The mixture was heated under reflux for ca. 30 minutes and then it was cooled to room temperature. The solid was recovered by filtration and then it was recrystallized from ethanol. This afforded 26.5 g of the title compound as fluffy, colorless crystals, m.p. 144.5°-145.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:18][C:19]([OH:21])=O)[CH:15]3[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:17][CH:9]2[CH2:10]4)[CH2:14]3)=[CH:4][CH:3]=1.[Cl-].[NH4+].O.O[N:26]1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:18][C:19]([NH2:26])=[O:21])[CH:15]3[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:17][CH:9]2[CH2:10]4)[CH2:14]3)=[CH:4][CH:3]=1
Reactant: O=C(O)CC1(c2ccc(Cl)cc2)C2CC3CC(C2)CC1C3
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)CC1(c2ccc(Cl)cc2)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of 2-[2-(4-chlorophenyl)adamantan-2-yl] acetic acid (100 mg, 0.33 mmol) in 4 mL N,N-dimethylformamide (DMF) were added sequentially ammonium chloride (88 mg, 1.6 mmol), 1-hydroxybenzotriazole hydrate (HOBt, 67 mg, 0.49 mmol), N,N-diisopropylethylamine (575 μL, 3.3 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 95 mg, 0.49 mmol). The mixture was stirred at room temperature under nitrogen for 2 h, then added to a separatory funnel containing 50 mL of ethyl acetate and aqueous hydrochloric acid (HCl, 1N). The layers were separated and the organic layer was washed sequentially with aqueous N HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to yield 82 mg of title compound as a white powder which was used without purification.
Reaction SMILES: C12BC(CCC1)CCC2.Br[C:11]1[N:20]([CH2:21][CH:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:23]=[CH2:24])[C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]=2[C:12]=1[C:33]1[CH:34]=[N:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2.[OH-].[Na+].ClCCl>C1COCC1.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].O>[Si:26]([O:25][CH:22]1[CH2:23][CH2:24][C:11]2[N:20]([C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]=3[C:12]=2[C:33]2[CH:34]=[N:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:21]1)([C:29]([CH3:32])([CH3:30])[CH3:31])([CH3:27])[CH3:28]
Reactant: C=CC(Cn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)O[Si](C)(C)C(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 0.5 M 9-borabicyclo[3.3.1]nonane in THF (50 ml) was added to a solution of 6-bromo-7-(2-(tert-butyldimethylsilyloxy)-3-butenyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.26 g) obtained in Step 6 in THF (30 ml) under ice-cooling. The mixture was stirred at room temperature for 4 hours. After slowly adding a 3 N aqueous sodium hydroxide solution (19.5 ml) to the reaction mixture at room temperature, a [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (676 mg) was added to the reaction mixture. The mixture was stirred under a nitrogen atmosphere at 70° C. for 4 hours. After cooling, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a yellow, oily substance (778 mg).
Reaction SMILES: C[C:2](C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][C@@H:15]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@H:17]([C@@H:18]([CH2:42][CH3:43])[C@@H:19]([OH:41])[C@@H:20]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C@H:21]3[CH2:22][C@@H:23]([OH:40])[C@@H:24]2[C@H:25]([CH3:30])[CH2:26][CH2:27][CH2:28][OH:29])[CH2:16]1.CO>CC(C)=O>[O:14]=[C:15]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@H:17]([C@@H:18]([CH2:42][CH3:43])[C:19](=[O:41])[C@@H:20]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C@H:21]3[CH2:22][C:23](=[O:40])[C@@H:24]2[C@H:25]([CH3:30])[CH2:26][CH2:27][C:28]([O:3][CH3:2])=[O:29])[CH2:16]1
Reactant: CC[C@H]1[C@@H](O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCCO)[C@H](O)C[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC[C@H]1C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)OC)C(=O)C[C@@H]23)[C@@]2(C)CCC(=O)C[C@@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Jones reagent (2 ml) was added dropwise to a stirred solution of the tetrol 7 (0.19 g, 0.45 mmol) in acetone (25 ml) at 0° C. and the mixture was stirred at room temperature for 1 h. Methanol (8 ml) was then added and the oxidized product was extracted with EtOAc (2×50 ml). The combined organic layers were dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue was dissolved in MeOH (80 ml), pTSA was added and the mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduce pressure, the residue was dissolved in CHCl3 (50 ml), washed with a saturated aqueous solution of sodium bicarbonate (2×50 ml), water (50 ml) and brine (50 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography using from 20 to 30% EtOAc in petroleum ether to afford the methyl ester 8 (0.115 g, 0.26 mmo, 58%1) as whitish solid.