Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[S:19])[C@@H:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[I-].[Na+].II.Cl[Si](C)(C)C>CCCCCC.C(#N)C>[CH2:13]([C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]([OH:2])=[S:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC[C@H](CCCCCC)C(=S)OC
Agent: C[Si](C)(C)Cl
Agent: II
Agent: [I-]
Solvent: CCCCCC
Solvent: CC#N
Product: CCCCCCCC[C@H](CCCCCC)C(O)=S
Temperature: 55 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a 12 L flask equipped with a condenser and overhead stirrer was added (S)-methyl-2-hexylthiodecanoate (302.5 g, 1.00 mol), and 3 L of dry acetonitrile. To this solution was added sodium iodide (600 g, 4.00 mol) and iodine (25.4 g, 0.10 mol) followed by chlorotrimethylsilane (543 g, 635 ml, 5.00 mol). The reaction was heated to an internal temperature of 55° C. After 12 hours, an additional portion of chlorotrimethylsilane (130 g, 152 mL, 1.20 mol) was added and heating continued for 8 hours. The reaction was cooled to 0° C., 6 L of hexane was added followed by 1 L of ice water, and the layers were allowed to separate. The top hexane layer was separated and set aside. The combined CH3CN/water layers were extracted with hexane (2×6 L). The combined hexane layers were washed with 1 L of water, 0.1M Na2S2O3 (2×3 L) and once with 3 L of 1:1 brine/water. The combined hexane extracts were dried with MgSO4, filtered and concentrated to give (S)-2-hexylthiodecanoic acid (260 g, 0.90 mol, 90%) a colorless oil: [α]D =-59.40° (C=1, MeOH); 1H NMR δ3.19 (m, 1H), 2.63 (m, 2H), 1.95-1.18 (m, 22H), 0.95 (m, 6H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[C:15]2[CH:34]=[CH:33][CH:32]=[CH:31][C:16]=2[C:17]2[CH2:18][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:20](=[O:23])[C:21]=2[CH:22]=1.IC.[Cl-].[NH4+]>O1CCCC1>[Br:13][C:14]1[C:15]2[CH:34]=[CH:33][CH:32]=[CH:31][C:16]=2[C:17]2[CH:18]([CH3:1])[N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:20](=[O:23])[C:21]=2[CH:22]=1
Reactant: O=C1c2cc(Br)c3ccccc3c2CN1c1ccccc1F
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1c2c(cc(Br)c3ccccc23)C(=O)N1c1ccccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (0.30 mL, 2.1 mmol) in 1 mL of tetrahydrofuran cooled to 0° C. was added n-butyllithium (2.5 M tetrahydrofuran solution, 0.93 mL, 2.3 mmol) dropwise. After 30 min, the mixture was added to a −78° C. solution of 5-bromo-2-(2-fluorophenyl)-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.150 g, 0.421 mmol) in 2 mL of tetrahydrofuran. After stirring for 30 min at −78° C., iodomethane (0.026 mL, 0.42 mmol) was added dropwise and after an additional 1 hr, the mixture was warmed to ambient temperature, treated with saturated aqueous ammonium chloride, and extracted 2× with ethyl acetate. The combined organic extracts were washed with water and brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the 5-bromo-2-(2-fluorophenyl)-1-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one that gave a proton NMR spectra consistent with theory.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>CO>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8]
Reactant: OCCNCCO
Reactant: C=C1CC(=O)O1
Solvent: CO
Product: CC(=O)CC(=O)N(CCO)CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A solution of 52.53 g (0.50 mol) diethanolamine in 100 ml MeOH was added dropwise to a solution of 40.00 g (0.48) diketene in 100 ml MeOH at 0° C. After stirring for 1 hour at 0° C., no starting material was detected anymore by thin-layer chromatography. The reaction mixture was spun off and the residue was purified by means of column chromatography. 81.32 g of product was obtained as a slightly yellow oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C([O-])([O-])=O.[Na+].[Na+]>CN1CCCC1=O.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CCCCCCCCNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCCCCCCNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(C)C
Yield: 85 %

Procedure:
The organic layer containing Z-Leu-Phe-NH-(CH2)7-CH3 was diluted with 1-methyl-2-pyrrolidinone and subjected to catalytic hydrogenolysis in the presence of palladium on charcoal. Upon completion of the reaction, 5% Na2CO3/10% NaCl was added and the resulting suspension was filtered at 45° C. The residue was washed with ethyl acetate, and the combined organic filtrates were extracted with 5% Na2CO3/10% NaCl, 30% NaCl and water. The organic layer was evaporated to dryness to give the desired product in 85% yield.
Reaction SMILES: C1(CC(O)=O)C=CC=CC=1.C[Si](C)(C)[C:13]1[CH:14]=[C:15]([CH2:19][C:20]([P:22](=[O:27])([O:25][CH3:26])[O:23][CH3:24])=[O:21])[CH:16]=[CH:17][CH:18]=1>>[C:15]1([CH2:19][C:20]([P:22](=[O:27])([O:23][CH3:24])[O:25][CH3:26])=[O:21])[CH:14]=[CH:13][CH:18]=[CH:17][CH:16]=1
Reactant: COP(=O)(OC)C(=O)Cc1cccc([Si](C)(C)C)c1
Agent: O=C(O)Cc1ccccc1
Product: COP(=O)(OC)C(=O)Cc1ccccc1

Procedure:
This compound was prepared from phenylacetic acid (0.68 g, 5.0 mmol) as described for the preparation of the trimethylsilyl analogue 50a. The reaction furnished 1.17 g of 50b as a white solid, mp. 117-122° C. (hygroscopic). IR (film): 3600-2600, 1457, 1312, 1237 and 1053; 1H NMR (200 MHz, CDCl3): δ3.83 (6H, d, J=11 Hz), 6.07 (1H, d, J=12 Hz) and 7.52 (5H, m); 13C NMR (50 MHz, CDCl3): δ53.6, 116.3, 116.8, 127.2, 127.3, 127.9, 129.2, 133.7, 134.1, 137.8 and 141.9; 31P (202 MHz; CDCl3; H3PO4): δ16.1; HR-MS (EI): mi/e 228.0550 (M+C10H13O4P requires 228.0551).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([O:9]CC)=[O:8])[CH2:2]1.[Li+].[OH-]>CO.O>[C:15]([O:14][C:12]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of (R)-1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (2.2 kg, 8.469 mol, 1 eq) in 5 L of MeOH was added a solution of LiOH (629.6 g, 15 mol, 1.77 eq) in 7.5 L of water at 0-5° C. After addition, the mixture was stirred overnight at room temperature. TLC showed the starting material was consumed. The pH of the system was adjusted to 7 by addition of saturated citric acid solution. Most of the methanol was removed. The pH was adjusted to 4-5 with citric acid. The mixture was extracted 3 times with 5 L of CH2Cl2, the organic layers were combined and dried over Na2SO4 and evaporated to afford a white solid (1.775 kg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.C(OC(=O)[NH:36][CH2:37][CH2:38][NH2:39])(C)(C)C.Cl>>[ClH:1].[NH2:36][CH2:37][CH2:38][NH:39][C:12](=[O:13])[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[CH2:21][CH2:22]2)=[O:16])=[CH:7]1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3F)CC2)c2ccc(Cl)cc21
Agent: Cl
Product: NCCNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure I, the coupling of {6-chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (preparation described herein), with (commercially available) (2-amino-ethyl)-carbamic acid tert-butyl ester gave, after treatment with HCl the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.Br[C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=1>>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=2)=[CH:3][CH:4]=1
Reactant: OCc1ccc(S)cc1
Reactant: N#Cc1ccc(Br)cn1
Product: N#Cc1ccc(Sc2ccc(CO)cc2)cn1
Yield: 28.4 %

Procedure:
Using the method of Preparation 155 using (4-mercaptophenyl)methanol (10.0 g, 71.3 mmol) and 5-bromopicolinonitrile (13.0 g, 71.3 mmol) affords the title compound (4.90 g, 28%).): 243 (M+H, 100%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1.CO.N.C(Cl)Cl>>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[CH2:20][NH:19][CH2:18][CH2:17][CH2:16][NH:15][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1
Reactant: COc1cc(Cl)nc2cccc(Cl)c12
Reactant: NCCCNCc1ccc(Cl)c(Cl)c1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc(NCCCNCc2ccc(Cl)c(Cl)c2)nc2cccc(Cl)c12
Temperature: 100 °C

Procedure:
A mixture of 2,5-dichloro-4-methoxyquinoline (0.12 g, 0.53 mmol) and N-(3-aminoprop-1-yl)-3,4-dichlorobenzylamine (0.37 g) was heated at 100° C. for 8 h. The resulting mixture was submitted to column chromatography (silica gel, MeOH:NH3:CH2Cl2 10:1:150→10:1:100) to give the title compound as a colourless film, (93 mg, 41%). δH (CDCl3) 1.70-1.87 (m, 3H+H2O), 2.74 (t, J=6.3, 2H), 3.54-3.65 (m, 2H), 3.72 (s, 2H), 3.91 (s, 3H), 5.22 (br, t, 1H), 5.90 (s, 1H), 7.10-7.17 (m, 2H), 7.28-7.37 (m, 2H), 7.40-7.45 (m, 2H); MS (ES+) 424 (MH+, 37%), 249 (100).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](O)=[O:40])[CH:34]=1)C1C=CC=CC=1.[NH2:42][CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>>[N:46]1([CH2:45][CH2:44][CH2:43][NH:42][C:39]([C:35]2[CH:34]=[C:33]([C:10]3[CH:11]=[C:12]([C:23]4[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=4)[C:13]([OH:15])=[CH:14][C:9]=3[OH:8])[CH:38]=[CH:37][CH:36]=2)=[O:40])[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1
Reactant: NCCCN1CCOCC1
Reactant: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)NCCCN3CCOCC3)c2)c(O)cc1O

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-biphenyl-3-carboxylic acid and N-(3-aminopropyl) morpholine as described in general procedure D. LCMS: 497 [M+H].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[CH:11][C:10]([O:13][C@H:14]([CH3:20])[C:15](OCC)=[O:16])=[CH:9][CH:8]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.C(OCC)C.O>[C:7]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:8]=[CH:9][C:10]([O:13][C@H:14]([CH3:20])[CH2:15][OH:16])=[CH:11][CH:12]=1
Reactant: CCOC(=O)[C@@H](C)Oc1ccc(-c2ccccc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CO)Oc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
Lithium aluminium hydride (86.67 ml, 1.0 M solution in tetrahydrofuran) was added dropwise to a stirred solution of (2R)-2-(biphenyl-4-yloxy)propanoic acid, ethyl ester (11.79 g, Example 1a) in dry tetrahydrofuran (200 ml) at 0° C. The resulting solution was stirred at room temperature under nitrogen for 3 hours. Water (3.3 ml), then aqueous sodium hydroxide (50% solution, 3.3 ml) then water (9.9 ml) were cautiously added to the solution at 0° C. Diethyl ether (200 ml) and anhydrous magnesium sulfate (20 g) were added and the solution stirred at room temperature for 20 minutes. The solution was filtered and the filtrate concentrated under reduced pressure to give the sub-title compound as a solid (9.43 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].C(O)C.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26]>C(N(CC)CC)C>[Cl:16][C:9]1[N:8]=[C:7]([CH3:17])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])[C:10]=1[N+:13]([O-:15])=[O:14]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CN(C)CCCN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NCCCN(C)C
Reaction time: 0.17 h

Procedure:
139.5 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.5 Mol.) in 500 ml. of ethyl alcohol are heated at reflux temperature. 60 g. of triethylamine are added and then 51 g. of 3-(dimethylamino)propylamine are slowly dropped in with stirring. After the addition is completed, heating is continued for 10 minutes. The solvent is distilled off and the residue is treated with 200 ml. of water and made alkaline (pH 9-10) with sodium hydroxide. The mixture is extracted three times with 150 ml. portions of ether. The organic layers are combined, dried over calcium chloride and evaporated to dryness. The residue is recrystallized from methanol, yield 110 g. (64%), m.p. < 20°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[F-].[Cs+].Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21].C1(C)C=CC=CC=1>CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccccc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: 110 °C
Yield: 94.2 %

Procedure:
A solid mixture of 4-methylphenylboronic acid (204 mg, 1.5 mmol), CsF (456 mg, 3.0 mmol), Pd(dba)2 (3 mg, 5 μmol), and ligand 1 (5 mg, 15 μmol) was thoroughly evacuated and purged with argon. 2′-Chloroacetophenone (0.13 mL, 1.0 mmol) and toluene (4 mL) were added and the reaction was heated at 110° C. for 1 h. GC-MS analysis indicated the reaction to be complete, i.e. starting aryl chloride reagent was completely consumed (quantitative GC yield). The reaction was taken up in ether (100 mL) and washed with H2O (30 mL) and brine (30 mL), The organic phase was dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel using hexanes:ethyl acetate (8:1) as eluant to afford the title compound as a yellow oil (198 mg, 92% isolated yield) after drying under vacuum. TON≈100 and TOF≈100. 1 H NMR (CDCl3): δ7.52 (d, J=8.4, 1H, ArH), 7.47 (d, J=7.2, 1H, ArH), 7.38 (t, J=7.2, 2H, ArH), 7.22 (s, 4H, ArH), 2.39 (s, 3H, C(O)CH3), 2.00 (s, 3H, ArCH3). 13C{1H} NMR (CDCl3): δ205.1, 140.9, 140.5, 137.8, 137.7, 130.6, 130.2, 129.4, 128.7, 127.8, 127.2, 30.4, 21.2.
Reaction SMILES: OC1C2N=N[NH:7][C:6]=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[O:23]1[C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=O)[C:27]=2[O:26][CH:25]=[CH:24]1.CN>CN(C=O)C.C1C=CC=CC=1.ClCCl>[CH3:6][NH:7][C:36](=[O:38])[CH2:35][CH2:34][CH2:33][C:32]1[C:27]2[O:26][CH:25]=[CH:24][O:23][C:28]=2[CH:29]=[CH:30][CH:31]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)CCCc1cccc2c1OC=CO2
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CNC(=O)CCCc1cccc2c1OC=CO2

Procedure:
0.1 g (0.75 mmol) of hydroxybenzotriazole (HOBt) and 0.14 g (0.75 mmol) of 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) are introduced at 0° C. into a reaction mixture comprising 0.15 g (0.68 mmol) of the acid obtained in Step F dissolved in 3 ml of anhydrous DMF. After the addition of 1.02 mmol of a 10% solution of methylamine in benzene, stirring is maintained for 24 hours and then the solvent is evaporated off in vacuo. The residue obtained is taken up in dichloromethane and then washed with water. The organic phase is dried over magnesium sulphate and then concentrated in vacuo. Chromatography over silica gel (eluant:AcOEt/PE:70/30) allows isolation of the title amide in the form of a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[N:17]=[C:18](Cl)[S:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[N:17]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2csc(Cl)n2)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2csc(-c3ccccc3)n2)c1

Procedure:
The chloro thiazole (114) (80 mg, 0.24 mmol) was coupled to phenylboronic acid (32 mg, 0.26 mmol) using Method E, except that the reaction mixture was heated for a total of 4 h. The crude residue was purified by column chromatography eluting with 25% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][CH:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][CH:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1)=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(N)cc1C(NC(C)=O)CC2
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1ccc(NC(=O)[C@H](C)NC(=O)OCc3ccccc3)cc1C(NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
A solution of N-benzyloxycarbonyl-(L)-alanine (63 mg, 0.28 mmol) in dichloromethane (4 ml) at −20° C. was treated with N-[3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide (100 mg, 0.28 mmol), (V. Fernholz Justus Liebigs Ann., 1950, 568, 63–72), and 1,3-dicylcohexylcarbodiimide (134 mg, 0.31 mmol) and the solution stirred for 16 hours at ambient temperature. Solvent was evaporated under reduced pressure and the residue chromatographed on silica gel, eluting with ethyl acetate to give a white solid which was triturated with diethyl ether. The title compound (85 mg) was obtained as a white solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12.N1C(C)=CC=CC=1C.[C:38]([NH:57][C:58]1[S:62][C:61]([CH2:63][C:64](O)=[O:65])=[N:60][N:59]=1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl.O.O1CCCC1.C(OCC)(=O)C.CN(C)C=O>[C:38]([NH:57][C:58]1[S:62][C:61]([CH2:63][C:64]([NH:2][CH:3]2[C:28](=[O:29])[N:5]3[C:6]([C:12]([O:14][CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]23)=[O:65])=[N:60][N:59]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(O)Cc1nnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3nnc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)s3)[C@H]2SC1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
To a suspension of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate monohydrochloride (2.15 g) in methylene chloride (100 ml) was added 2,6-lutidine (0.54 g) under ice-cooling. To the resultant solution were added 2-(5-tritylamino-1,3,4-thiadiazol-2-yl)acetic acid (2.4 g), N,N-dicyclohexylcarbodiimide (1.03 g), tetrahydrofuran (200 ml) and N,N-dimethylformamide (60 ml), and the mixture was stirred at ambient temperature for a day. Removal of the solvent gave a residue, to which a mixed solvent of ethyl acetate, tetrahydrofuran and water was added. The insoluble substances were removed by filtration, and the filtrate was washed with dilute hydrochloric acid, a saturated aqueous sodium bicarbonate and an aqueous sodium chloride, followed by drying over magnesium sulfate. Removal of the solvent gave a residue, which was washed with diisopropyl ether to obtain benzhydryl 7-[2-(5-tritylamino-1,3,4-thiadiazol-2-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (2.6 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[Li]CCCC.CN([CH:31]=[O:32])C>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:31]=[O:32])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 51.7 %

Procedure:
To a solution of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (1.96 g, 6.05 mmol) in THF (75 mL) was a 2.5 M solution of n-BuLi in hexanes (3.2 mL, 7.9 mmol) at −78° C. The reaction mixture was then stirred at −78° C. for 45 minutes. DMF (0.94 mL, 12.1 mmol) was then added. The resulting mixture was stirred at −78° C. for 2 hours before being poured slowly onto ice. The mixture was then extracted three times with DCM. The combined extracts were washed with water, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (25% EtOAc in heptane) to give the title compound (1.1 g, 52%). LCMS: M+H+=352.2.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1.C(O)(=O)C.S(=O)(=O)(O)O.C>O.C(OCC)(=O)C.C(Cl)Cl.O.S([O-])([O-])(=O)=O.[Mn+2].[O-2].[O-2].[O-2].[Cr+6]>[CH3:21][C@@H:11]1[CH2:10][C:9]2[C@H:4]([CH2:5][CH2:6][C:7](=[O:22])[CH:8]=2)[C@@H:3]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C:2]2=[O:1])([CH3:18])[C:16](=[O:20])[CH2:15][CH2:14]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@H]2O
Agent: [Cr+6]
Agent: [Mn+2]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2C(=O)C[C@]3(C)C(=O)CC[C@H]3[C@@H]21

Procedure:
A mixture of 11α-hydroxy-7α-methylestr-4-ene-3,17-dione (A, obtained from Fermentation) and acetic acid (7.5 ml) is stirred and cooled to about 10° in a cold water bath. The following reagents are added: water (6 drops), manganese sulfate monohydrate (0.1 g) in water (1 ml), chromium trioxide (0.66 g) in water (2 ml), and concentrated sulfuric acid (0.6 ml). The chromium trioxide solution is added over a 15 minute period. After 1/2 hour water (10 ml) is added and the crystals of the product are collected, washed with water and dried to give a solid. The solid is dissolved in hot ethyl acetate/methylene chloride (1/1) and decolorized with a little charcoal and silica gel and then filtered through celite. The appropriate fractions are pooled and concentrated to give crystals, UV (ethyl alcohol) λmax =239 nm (ε=16250); IR (mull) 1740, 1707, 1672 and 1616; MS (m/e)=300, 282, 272, and 258.