Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:24])[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[C:16](=[O:22])[CH2:15][C:14]1=[O:23].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH:15]2[C:14](=[O:23])[C:13]([CH3:24])([CH3:12])[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[C:16]2=[O:22])=[O:10])=[CH:4][CH:3]=1
Reactant: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)C(C(=O)Cc2ccc(Cl)cc2)C(=O)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chlorophenylacetic acid (1.7 g, 10 mmol) and oxalyl chloride (2 ml, 23 mmol) were stirred in 100 ml methylene chloride with two drops of dimethylformamide for two hours. The solvent and excess oxalyl chloride were removed under vacuum to give p-chlorophenylacetyl chloride. The 4-chlorophenylacetyl chloride and 4,4,6,6-tetramethyl-1,3,5-cyclohexanetrione (1.5 g, 8.2 mmol) were dissolved in methylene chloride. Triethylamine (3 ml) was added and the resulting solution stirred at room temperature for 30 minutes. The solution was washed with 1 normal hydrochloric acid (1N HCl), 5% potassium carbonate (5% K2CO3) and saturated sodium chloride (brine), dried over anhydrous magnesium sulfate (MgSO4) and concentrated under vacuum. The residue was dissolved in 15 ml acetonitrile. Triethylamine (3 ml) and acetone cyanohydrin (0.3 g) were added and the mixture stirred at room temperature for 4 hours. After dilution with ether, the solution was washed with 1N HCl and extracted with 5% K2CO3. The basic extract was acidified with hydrochloric acid and extracted with ether. The ether extract was washed with brine, dried (MgSO4) and concentrated under vacuum yielding 1.0 g of an oil that solidified on standing (m.p. 57°-61° C.). It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1[CH2:16][O:15]CC1>C(Cl)Cl>[NH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([CH2:16][O:15][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: C1CCOC1
Reactant: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCNC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To the Wang resin (12 g, 1.1 mmol/g) in a 250 mL peptide synthesis vessel was added 120 mL of 0.4 N CDl in anhydrous THF, and shaken at room temperature for 17 hours. The resin was thoroughly washed with CH2Cl2 (3×100 mL ) and THF (3×100 mL) to remove the excess CDl and then treated with 120 mL of 0.4 N 3-piperidinemethanol in THF at room temperature for 17 hours. The resulting resin 1 was washed with DMF (3×100 mL), MeOH (4×100 mL), and CH2Cl2 (4×100 mL) and dried in vacuo. To the alcohol resin 1 was added methanesulfonyl chloride (5.11 ml, 66 mmol) in 100 mL CH2Cl2 followed by 20 mL of pyridine, and the resulting slurry was shaken at room temperature for 17 hours. The resulting mesylate resin 2 was washed with DMF (3×100 mL), MeOH (4×100 mL), and CH2Cl2 (4×100 mL) and dried in vacuo.
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]=1[C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:48]([C:50]1[N:51]=[C:52]([C:63]([O-])=[O:64])[N:53]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[CH:54]=1)#[N:49].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:17]1([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:63]([C:52]2[N:53]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[CH:54]=[C:50]([C:48]#[N:49])[N:51]=2)=[O:64])[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: CN1C(=O)CC(c2ccc(N)c(C3=CCCCC3)c2)CC1=O
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1C(=O)CC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CC1=O
Yield: 26.6 %

Procedure:
A solution of 266 mg (0.891 mmol) of 4-(4-amino-3-cyclohex-1-enyl-phenyl)-1-methyl-piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 623 mg (1.34 mmol) of PyBroP, 300 mg (0.981 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 466 μL (2.67 mmol) of DIEA at RT for 16 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25% EtOAc-hexane afforded 130 mg (27%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C29H37N5O4Si, 548.3 (M+H). found 547.9.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:8]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@H:9]([C:11]([NH:13][C@H:14]([C:16]([NH:18][NH2:19])=[O:17])[CH3:15])=[O:12])[CH3:10].CN1CCOCC1.C(Cl)Cl>CN(C=O)C>[NH:8]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[C@H:9]([C:11]([NH:13][C@H:14]([C:16]([NH:18][NH:19][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:17])[CH3:15])=[O:12])[CH3:10]
Reactant: CCOC(=O)CBr
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)NN
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)CNNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
Ethyl bromoacetate (1.1 eq) was added dropwise to a stirred solution of Cbz-Ala-Ala-NHNH2 (1 eq) and NMM (1.1 eq) in DMF that was cooled to −10° C. The resulting solution was stirred for 30 min at −10° C., after which the mixture was allowed to react at room temperature for 36 hours. The DMF was evaporated, and the residue was purified on a silica gel column using 1:9 MeOH:CH2Cl2 as the eluting solvent system to afford 4a as a white solid (yield=36%). 1H NMR (DMSO-d6): 1.18 (t, 9H, CH3), 3.5 (d, 2H, NCH2COOEt), 4.0-4.15 (m, 3H, α-H and OCH2CH3), 4.2 (m, 1H), α-H), 5.03 (m, 2H, Cbz), 5.18 (m, 1H, NH), 7.22-7.40 (m, 5H, Ph), 7.4-7.5 (d, 1H, NH), 7.9 (m, 1H, NH), 9.35 (m, 1H, NH). MS (FAB) m/z 395 [(M+1)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:23][C:24]1[CH:25]=[C:26]([C:31]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]([NH2:38])[N:32]=2)[C:27](F)=[N:28][CH:29]=1>C1COCC1>[NH2:38][C:33]1[N:34]=[C:35]([CH3:37])[N:36]=[C:31]([C:26]2[C:27]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=3)=[N:28][CH:29]=[C:24]([Cl:23])[CH:25]=2)[N:32]=1
Reactant: Cc1nc(N)nc(-c2cc(Cl)cnc2F)n1
Reactant: CC(=O)Nc1ccc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Nc2ncc(Cl)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.7 %

Procedure:
A mixture of N-(4-amino-2-fluorophenyl)acetamide (0.084 g, 0.501 mmol) in THF (5 mL) was cooled to 0° C. under N2. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (Aldrich) (0.487 mL, 2.504 mmol) was added and the mixture was stirred at 0° C. for 30 min before 4-(5-chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.100 g, 0.417 mmol) was added. The resulting mixture was stirred at 0° C. for 10 min and then removed from the ice bath and stirred for 2 h. The reaction was quenched with sat. NH4Cl. The resulting mixture was partitioned between pH 7 buffer (1 M TRIS-HCl) and CHCl3. The aqueous layer was extracted with CHCl3 (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by prep HPLC. Fractions containing the product were combined and the solvent was removed in vacuo. The residue was basified using sat. NaHCO3 (10 mL). The aqueous layer was extracted with CHCl3 (3×15 mL). The combined organic layers were dried over MgSO4 and concentrated to give the product as a brown solid (40 mg). m/z (ESI, +ve ion) 388.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.08 (s, 1H); 9.63 (s, 1H); 8.75 (d, J=2.74 Hz, 1H); 8.43 (d, J=2.74 Hz, 1H); 7.93-8.06 (m, 2H); 7.88 (br. s., 1H); 7.71 (t, J=8.80 Hz, 1H); 7.45 (dd, J=8.80, 1.76 Hz, 1H); 2.45 (s, 3H); 2.06 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[F:13][C:14]([F:19])([F:18])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:14]([F:19])([F:18])[F:13]
Reactant: O=C([O-])C(F)(F)F
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc([N+](=O)[O-])ccc1C(F)(F)F
Temperature: 155 °C
Reaction time: 20 h
Yield: 72.1 %

Procedure:
To a solution of 1-bromo-2-methoxy-4-nitrobenzene (10.0 g, 43.0 mmol) in N,N-dimethylformamide (200 mL) were added potassium trifluoroacetate (13.0 g, 86.0 mmol), copper iodide(I) and toluene (40 mL), and the mixture was stirred at 155° C. for 20 hr while removing the produced water drops by a Dean-Stark trap. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was suspended in ethyl acetate (300 mL), the insoluble material was filtered off, and the filtrate was washed with water (150 mL) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=98/2→88/12). The obtained solution was concentrated under reduced pressure to give the title compound (6.86 g, 72%) as a pale-yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([NH:8][NH2:9])=[O:7].CO[C:12](OC)(OC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[C:13]1([C:12]2[N:1]3[CH:5]=[CH:4][N:3]=[C:2]3[C:6](=[O:7])[NH:8][N:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(OC)(OC)c1ccccc1
Reactant: NNC(=O)c1ncc[nH]1
Solvent: CCO
Product: O=c1[nH]nc(-c2ccccc2)n2ccnc12
Reaction time: 0.17 h

Procedure:
A 2.6 gm. portion of 2-imidazolecarboxylic acid hydrazide is added to 200 ml. of ethanol. To this is added 20 ml. of trimethylorthobenzoate. The mixture is refluxed for 31 hours, then the solvents are evaporated giving a white solid which is washed twice with diethyl ether giving 3.0 gm. of white solid. This solid is combined with 50 ml. of diphenyl ether and heated with stirring in an oil bath at 265°-275° C. for 10 minutes. The mixture is cooled, petroleum ether is added and the mixture is filtered. The solid is washed twice with hot petroleum ether, giving 1.4 gm. of the desired product as a light tan solid, m.p. 292°-295° C.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH3:24])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].O.[CH:26]([CH:28]=O)=O.O>C(O)CCC>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[NH:10][C:11](=[O:14])[C:12]2[C:7](=[N:6][CH:26]=[CH:28][N:13]=2)[N:8]=1)[CH2:23][CH3:24]
Reactant: O=CC=O
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Solvent: O
Product: CCCOc1ccccc1-c1nc2nccnc2c(=O)[nH]1
Yield: 97.5 %

Procedure:
A stirred mixture of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one sulphate (1.25 g), glyoxal hydrate (0.4 g), water (62.5 ml) and n-butanol (1 ml) was heated under reflux for one hour to afford a crude product (0.97 g) which was collected and washed with water. The crude product together with another sample (0.12 g) similarly prepared was eluted from a silica column with chloroform. The combined fractions containing product were evaporated under reduced pressure to afford a solid (0.96 g) which was recrystallized from ethanol-water to afford the title compound, 0.8 g, m.p. 177.5-178.5° C.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH3:23])[CH:12]=O.C([CH2:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:29])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:16]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:27]/[C:28]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])=[CH:10][C:9]=1[O:8][CH3:7])[CH2:19][C:20]#[C:21][CH2:22][CH3:23]
Reactant: CCC#CCCOc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCC#CCCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 63.5 %

Procedure:
Piperidine (0.17 mL, 1.7 mmol) was added to a suspension of 3-methoxy-4-(hex-3-ynyloxy)benzaldehyde (0.40 g, 1.7 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.35 g, 1.6 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH providing (E)-2-[[3-(4-(hex-3-ynyloxy)-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.40 g, 65%) as a colourless crystalline solid; mp 165-166° C.; δH (400 MHz, DMSO-d6) 1.04 (t, J=7.6 Hz, 3H, CH3), 2.14 (q, J=7.6 Hz, 2H, CH3CH2), 2.61 (t, J=7.6 Hz, 1H, OCH2CH2C), 3.83 (s, 3H, OCH3), 4.05 (t, J=7.6 Hz, 2H, OCH2), 6.79 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.22 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.38 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.99 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.57 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 11.7, 14.0, 19.2, 55.7, 66.9, 76.1, 83.0, 110.9, 113.0, 116.6, 120.1, 120.3, 122.5, 122.6, 127.6, 131.1, 134.0, 141.0, 141.5, 149.1, 149.5, 164.1, 169.4; HRMS (ESI) calculated for C23H23NO5 [M+H]+ 394.1649. found 394.1647; vmax 755, 1235, 1510, 1601, 1669, 3234, 3563 cm−1.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>CCO>[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cccnc1-c1ccc(F)cc1
Temperature: 78 °C
Reaction time: 8 h

Procedure:
To a nitrogen purged flask was charged Pd(Ph3)4 (1.84 g, 1.6 mmoles, 0.005 eq), sodium carbonate (42.8 g, 404 mmoles, 1.3 eq), 52 (55.5 g, 320.6 mmoles, 1.0 eq), p-fluorophenylboronic acid (53.8 g, 384.7 mmoles, 1.2 eq), followed by 1.3 L denatured EtOH. The reaction was heated to 78° C. with vigorous stirring under N2 overnight. HPLC analysis [Tret 52=10 min, Tret 54=12 min] of the reaction mixture showed that the starting material was completely consumed and a later-eluting peak produced. The reaction was cooled to room temperature and the solvents removed under vacuum. The residue was dissolved in EtOAc, washed, dried (MgSO4), filtered through celite, and concentrated to afford a pale yellow solid 54.
Reaction SMILES: [C:1]12([CH2:12][C:11](=O)[O:10][C:8](=[O:9])[CH2:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.[BH4-].[Na+].O.Cl>C1COCC1>[CH2:7]1[C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:12][CH2:11][O:10][C:8]1=[O:9]
Reactant: O=C1CC2(CCCCC2)CC(=O)O1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC2(CCCCC2)CCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 1,1-cyclohexane diacetic acid anhydride (20.1 g) in THF (150 mL) was added sodium borohydride (3.78 g, 100 mmol) under ice cooling. The reaction solution was stirred at room temperature for additional 3 hours. Water was added to the solution, and it was made acidic with conc. hydrochloric acid. The solution was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was then concentrated under reduced pressure to give the title compound (17.07 g). This product was subjected to the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C)=[O:10])=[C:4]([C:13]#[C:14][Si](C)(C)C)[CH:3]=1.C1COCC1.CO.O.[OH-].[Li+]>O>[C:13]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([OH:11])=[O:10])#[CH:14]
Reactant: COC(=O)Cc1ccc(F)cc1C#C[Si](C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cc(F)ccc1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a solution of ester 326 (3.30 g, 12.5 mmol) in 1:1 THF/methanol (100 mL) was added lithium hydroxide monohydrate (1.60 g, 38.1 mmol) in water (25 mL) and the mixture was stirred at r.t. for 30 min. It was then partially concentrated; the aqueous residue was washed with ether; then acidified with 3M HCl (aq), extracted with ethyl acetate. The organic extract was washed with water, dried (anhydrous MgSO4), filtered and concentrated to provide acid 327 (2.10 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.36 (dd, J=8.6, 5.9 Hz, 1H); 7.30 (dd, J=9.2, 2.7 Hz, 1H); 7.21 (dt, J=8.6, 2.7 Hz, 1H); 4.48 (s, 1H); 3.70 (s, 2H). LCMS: (M+Na) 201.1.
Reaction SMILES: N[C:2]12[CH:18]([OH:19])[CH2:17][CH:9]([C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][C:15]=31)[C:8]1[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].N([O-])=O.NO>C(O)(=O)C.O.C(OCC)(=O)C>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]2[CH:9]3[CH2:17][C:2]([CH:18]=[O:19])([C:3]4[C:8]3=[CH:7][CH:6]=[CH:5][CH:4]=4)[C:15]=2[CH:14]=1
Reactant: NC12c3ccccc3C(CC1O)c1ccc(Cl)cc12
Agent: NO
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Temperature: 10 °C
Reaction time: 4 h
Yield: 53.6 %

Procedure:
(9RS,10RS,12RS)-9-Amino-2-chloro-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene prepared as in Example 1i (445.5 g, 1.64 moles) was dissolved in glacial acetic acid (4.0 L), and the resulting solution cooled to 10° C. A solution of sodium nitrite (340.0 g, 4.93 moles) in water (1.4 L) was added to the reaction mixture over a period of 1.75 h. The temperature of the mixture was maintained at 10° C. during the addition of the nitrite, and for 4 h thereafter. The mixture was then stirred overnight and allowed to warm to room temperature. TLC analysis [silica gel/toluene:ethyl acetate (4:1)] showed complete conversion of the amino alcohol (Rf =0.12) to the desired aldehyde (Rf =0.80). The reaction mixture was diluted with water (4 L) which caused precipitation of a reddish-brown tar. The aqueous supernatant was decanted away from the tar, diluted with an equal volume of crushed ice, then adjusted to pH=5-6 with solid sodium hydroxide. The resulting aqueous mixture was extracted with ethyl acetate (3×1.5 L). The combined ethyl acetate extracts were used to redissolve the tar, and the resulting solution washed with brine (2×1 L) then dried over magnesium sulfate. Filtration, followed by removal of the solvent in vacuo, gave the crude product as a thick brown oil. Purification of this material by column chromatography over silica gel, eluting with a solvent mixture of methylene chloride:hexane (1:1), afforded a thick yellow oil which crystallized on standing (311.7 g, 74.6%). Trituration with diethyl ether:hexane (1:6-700 ml) gave a first crop of pure title compound as an off-white crystalline solid (224.1 g, 53.6%), mp 91°-92° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#N.[OH-:9].[K+].[OH2:11]>C(OCC)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:11])=[O:9]
Reactant: N#CCc1ccco1
Reactant: O
Reactant: [OH-]
Agent: [K+]
Solvent: CCOCC
Product: O=C(O)Cc1ccco1

Procedure:
2-(Furan-2-yl)acetonitrile was suspended in 300 mL of distilled water, mixed with 50 g (0.89 mmol) of potassium hydroxide and heated for 4 hours under reflux. After completion of the reaction, the reaction solution was diluted with diethyl ether and separated. The resulting aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filterd, and the filtrate was concentrated under reduced pressure to give 25.2 g of the desired product.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:16]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[N+]=[N-].[H][H].[CH2:19]([OH:21])[CH3:20]>[Pd]>[O:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][NH:1][C:19](=[O:21])[CH3:20])[C:16]=2[O:15][CH2:14][CH2:13]1
Reactant: CCO
Reactant: [H][H]
Reactant: [N-]=[N+]=NCCCc1cccc2c1OCCO2
Agent: [Pd]
Product: CC(=O)NCCCc1cccc2c1OCCO2

Procedure:
The amine is first of all synthesised by catalytic hydrogenation of the compound obtained in Step A. The latter (900 mg; 4.1 mmol) is dissolved with ethanol (15 ml) in the reactor of a Paar apparatus. After the addition of the catalyst, in this case 10% palladium on carbon (90 mg; 10% by weight), stirring is maintained for 4 hours at room temperature at a hydrogen pressure of 45 psi. The reaction mixture is filtered and then concentrated under reduced pressure, and the amine is recovered in the form of a colourless oil. The latter is of the correct purity according to thin-layer chromatography and will thus be acetylated directly under the conditions of Step C of Example 1. Pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O.S(O)(O)(=O)=O.O[NH:76][C:77]([NH2:79])=[NH:78].ONC(N)=N>CN(C=O)C>[NH2:79][C:77]1[N:78]=[C:24]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:76]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reactant: N=C(N)NO
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C2CC(c3nc(N)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, a solution of 2.50 g (6.31 mmol) of the carboxylic acid from Example 21A in 50 ml of DMF was admixed at RT with 3.94 g (7.57 mmol) of PYBOP and 2.20 ml (12.6 mmol) of N,N′-diisopropylethylamine. Subsequently, the mixture was stirred at RT for 30 min and then the solution was added dropwise within 1.5 h to a suspension of 5.04 g (18.9 mmol) of hydroxyguanidine hemisulphate hemihydrate, 3.30 ml (18.9 mmol) of N,N′-diisopropylethylamine and 4 Å molecular sieve. The reaction mixture was stirred at RT for 1 h and then filtered through a frit. The residue was washed with 50 ml of DMF and then the combined organic phases were stirred at 130° C. (preheated oil bath) for 40 min. Subsequently, the solvent was removed under reduced pressure and the residue was admixed with 30 ml of diethyl ether and 30 ml of 1 N aqueous sodium hydroxide solution, and stirred vigorously for 24 h. The organic phase was removed and the aqueous phase was extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 3.00 g (77% of theory, purity 65%)