Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH2:12])[CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[C:4]([NH2:12])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cc(N)c(C(=O)O)cc1C
Product: COC(=O)c1cc(C)c(C)cc1N

Procedure:
0.41 g Sodium nitrite in water is added to 1 g 4,5-dimethyl-2-nitroaniline in 3 mL conc. HCl and stirred for 1 hour at +4° C. This solution is added to a mixture of 0.67 g copper (I) cyanide, 0.98 g sodium cyanide, 0.32 g sodium carbonate, 25 mL of water and 3 mL toluene. The mixture is stirred for 12 hours at room temperature and worked up to give 0.45 g 4,5-dimethyl-2-nitrobenzonitrile. 4,5-Dimethyl-2-nitrobenzonitrile is reduced with iron powder in acetic acid to yield 4,5-dimethyl-2-aminobenzonitrile. 4,5-Dimethyl-2-aminobenzonitrile is heated at reflux for 12 hours in conc. HCl to give 4,5-dimethyl-2-aminobenzoic acid. 4,5-Dimethyl-2-aminobenzoic acid is reacted with trimethylsilyl-diazomethane to yield methyl 4,5-dimethyl-2-aminobenzoate (Chem. Pharm. Bull. Vol. 29, 1475 (1981)).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][C:49]=1[F:50])[O:31][C:32]1[CH:44]=[CH:43][C:35]2[N:36]=[C:37]([NH:39][C:40](=[O:42])[CH3:41])[S:38][C:34]=2[C:33]=1[C:45]#[N:46]>O1CCCC1.C(OCC)(=O)C>[C:40]([NH:39][C:37]1[S:38][C:34]2[C:33]([C:45]#[N:46])=[C:32]([O:31][C:30]3[CH:47]=[CH:48][C:49]([F:50])=[C:28]([NH:27][C:4](=[O:6])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[C:2]=4[Cl:1])[CH:29]=3)[CH:44]=[CH:43][C:35]=2[N:36]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(N)c3)c(C#N)c2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (156 mg, 0.697 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (75 μL, 0.875 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Amino-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (200 mg, 0.584 mmol) was added to the solution, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (20 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was successively purified by basic silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0) and silica gel column chromatography (ethyl acetate/n-hexane=70/30→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (164 mg, 51%) as a white powder. 1H-NMR (DMSO-d6, 300 MHz) δ 1.84 (6H, s), 2.24 (3H, s), 7.07 (1H, dt, J=8.8, 3.4 Hz), 7.16 (1H, d, J=9.0 Hz), 7.35-7.46 (1H, m), 7.47-7.61 (2H, m), 7.66 (1H, dd, J=7.7, 1.7 Hz), 7.81 (1H, dd, J=6.3, 3.1 Hz), 8.04 (1H, d, J=9.0 Hz), 10.65 (1H, s), 12.69 (1H, s).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.Br[C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][CH:16]=1.[NH4+].[Cl-]>CCOCC.C1COCC1.[Cl-].[Cl-].[Zn+2].Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([C:12]1[C:11]([C:4]2[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)#[N:18]
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: N#Cc1ncccc1Br
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(-c2cccnc2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of p-tolylmagnesium bromide (9.3 mL of a 1M solution in Et2O, 9.28 mmol) in THF (17 mL) at -78° C. was added ZnCl2 (9.3 mL of a 1M solution in Et2O, 9.28 mmol). The resulting slurry was warmed to rt for 20 min then cooled to 0° C. Bis-(triphenylphosphine)nickle(II) chloride (178 mg, 0.27 mmol) and 3-bromo-2-cyanopyridine (1.0 g, 5.5 mmol); (prepared as reported: Chem. Pharm Bull., 1985, vol. 33, p 565) were added in one portion. After 1 h, saturated aqueous NH4Cl (50 mL) was added and the mixture was extracted with EtOAc (2×50 mL). Purification by flash chromatography (40% EtOAc/hexanes) gave the above titled compound as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([O:46][CH3:47])=[O:45])=[CH:39][CH:38]=2)O1.Br[C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][C:51]=1[F:57].Cl>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:57][C:51]1[CH:52]=[C:53]([OH:56])[CH:54]=[CH:55][C:50]=1[C:37]1[CH:38]=[CH:39][C:40]([CH2:43][C:44]([O:46][CH3:47])=[O:45])=[CH:41][CH:42]=1
Reactant: Oc1ccc(Br)c(F)c1
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(-c2ccc(O)cc2F)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
After palladium acetate (II) (50 mg, 0.22 mmol), tri-o-tolylphosphine (135 mg, 0.44 mmol) and a 2N aqueous sodium carbonate solution (15 ml) were added to a solution of methyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (2.04 g, 7.39 mmol) obtained in Example (12-1) and 4-bromo-3-fluorophenol (1.69 g, 8.87 mol) in N,N-dimethylformamide (50 ml), the mixture was stirred at 80° C. for 3 hours. The reaction mixture was poured into 0.5N hydrochloric acid and the mixture was extracted with ethyl acetate (three times). The organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=80/20-50/50) to give methyl (2′-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (1.13 g, yield: 59%).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:12]N1C(=O)CCC1=O.OS(O)(=O)=O>C(O)(=O)C>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([I:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 88 h

Procedure:
To a stirred slurry of methyl 2-iodo-benzoate (5.0 g, 0.019 mol) and N-bromosuccinimide (3.74 g, 0.021 mol) in acetic acid (10 mL) was added concentrated H2SO4 (10 mL) dropwise, keeping the temperature at 20-40° C. The mixture was stirred at room temperature for 88 hours and then heated at 50° C. for 4 hours. The mixture was cooled to 10° C., treated with 40 g of ice water, and extracted with 50 mL of CH2Cl2. The organic phase was washed in succession with 2×50 mL 5% NaHCO3, 50 mL 10% Na2S2O3, 50 mL water, and concentrated to colorless oil. The residue was purified by column chromatography (silica gel, 10:90 EtOAc:hexane) to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.92 (d, J=4 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.27 (dd, J=8, 4 Hz, 1H), 3.92 (s, 3H); MS (DCI/NH3) [M+NH4]+ at 358, [M+NH3NH4]+ at 375.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([CH2:16][CH2:17][CH3:18])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[C:23]([O:22][C:20]([NH:19][C@H:13]1[C@@H:14]([CH2:16][CH2:17][CH3:18])[CH2:15][NH:11][CH2:12]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C

Procedure:
A mixture of (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-propylpyrrolidine (4.02 g, 11.09 mmol) and a 10% palladium carbon catalyst (1.0 g) in ethanol (100 mL) was stirred hard for 20 hours under an ordinary pressure in a hydrogen atmosphere. Insoluble matter was removed through filtration by use of Celite, and then ethanol was removed under reduced pressure. The residue was dissolved in diethyl ether (200 mL), and the solution was washed by a 1 mol/L aqueous sodium hydroxide solution (100 mL), followed by drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, to thereby yield the title compound as a colorless oily substance (2.34 g, 92.4%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][Se:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C(N(CC)CC)C>ClCCl.C(OCC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][Se:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)=[O:13]
Reactant: Nc1ccccn1
Reactant: O=C(O)c1ccccc1[Se]Cc1ccccn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Nc1ccccn1)c1ccccc1[Se]Cc1ccccn1
Reaction time: 20 h

Procedure:
To a solution of 5.84 g (0.02 mol) 2-(2-picolylseleno)benzoic acid (from Example 1) in 40 ml dichloromethane that has been cooled to 0° C. are added in one portion 5 g (0.02 mol) bis[2-oxo-3-oxazolidinyl]phosphoryl chloride. After stirring for 2 hours at room temperature 1.88 g (0.02 mol) 2-aminopyridine, 50 ml dichloromethane and 6.4 ml triethylamine are added dropwise in succession at 10° C. and stirring is continued at room temperature for 20 h. The reaction mixture is extracted twice with 100 ml portions of water, dried over sodium sulfate and the solvent removed. The brown oil (7 g) is taken up in 100 ml 1 N HCl, filtered, the filtrate basified with 13 ml 10 N sodium hydroxide and extracted with 100 ml ethyl acetate. The organic phase is dried, concentrated and the solid residue obtained is stirred for 48 h with 100 ml diethyl ether. After filtration the crude product is cleaned up by column chromatography (silica gel/dichloromethane) and recrystallized from 20 ml 2-propanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([CH:16]3[CH:20]([C:21]([O:23]CC)=O)[CH2:19][NH:18][CH2:17]3)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH2:8]([N:18]1[CH2:19][CH:20]([CH2:21][OH:23])[CH:16]([CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:17]1)[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(=O)C1CNCC1C(=O)N1CCC(c2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC1CN(Cc2ccccc2)CC1CN1CCC(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6.4 g (14.6 mmol) of 1-benzyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylcarbonyl)-4-(RS)-(ethoxycarbonyl)pyrrolidine in 60 mL of THF at 0° C. was added 17.5 mL (17.5 mmol) of a 1M solution of lithium aluminum hydride (LAH) in ether and the reaction was stirred at 0° C. for 30 min. The reaction mixture was quenched with 5N NaOH. The reaction mixture was extracted with ether and the combined organic fractions were washed with 5N NaOH solution. The organic fractions were dried over Na2SO4, filtered and the filtrate was purified by chromatography [silica, hexanes: ethyl acetate: (2N NH3 in MeOH), 10: 10: 1] to give 4.7 g of the title compound. Spectrum (ESI) m/e=383 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(Br)cc1Cl
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 4-bromo-2-chlorobenzoic acid (450 g) in N,N-dimethylformamide (3000 mL) were added potassium carbonate (792.4 g) and iodomethane (271 g) at 10° C., and the mixture was stirred at the same temperature for 2 hr. Iodomethane (54.3 g) was added, and the mixture was stirred at the same temperature for 1 hr. Iodomethane (27.2 g) was added again, and the mixture was stirred at the same temperature for 1 hr. Iodomethane (27.2 g) was further added, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was poured into water, and partitioned and extracted with ethyl acetate. The organic layer was washed with 25% brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (477 g) as a pale-yellow oil.
Reaction SMILES: [O:1]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[Cl-].[K+].[CH3:28][C@@H:29]1[CH2:46][C:45]2[C@H:40]([CH2:41][CH2:42][C:43](=[O:47])[CH:44]=2)[C@@H:39]2[C@@H:30]1[C@H:31]1[C@@:35]([CH2:37][CH2:38]2)([CH3:36])[C:34](=[O:48])[CH2:33][CH2:32]1>CN(C=O)C>[OH:1][C@@H:38]1[CH2:37][C@@:35]2([CH3:36])[C@@H:31]([CH2:32][CH2:33][C:34]2=[O:48])[C@H:30]2[C@H:39]1[C@@H:40]1[C:45]([CH2:46][C@H:29]2[CH3:28])=[CH:44][C:43](=[O:47])[CH2:42][CH2:41]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@@H]21
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Product: 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
Temperature: 28 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
A 2 l Erlenmeyer flask that contained 500 ml of a nutrient solution, sterilized for 30 minutes at 121° C. in an autoclave and consisting of 3% by weight of glucose, 1% by weight of corn steep liquor, 0.2% by weight of NaNO3, 0.1% by weight of KH2PO4, 0.2% by weight of K2HPO4, 0.05% by weight of KCl, 0.05% by weight of MgSO47H2O, and 0.002% by weight of FeSO47H2O (pH 6.0), was inoculated with a half slant rod culture of the strain Aspergillus ochraceus (CBS 13252) and shaken for 72 hours at 28° C. in a rotary shaker at 165 rpm. With this preculture, a 10 l fermenter was inoculated, and said fermenter was coated with 9.5 l of a sterile medium of the same final composition as described for the preculture. In addition, before the sterilization, another 0.5 ml of silicone oil and 0.5 ml of synperonic were added for foam abatement. After a growth phase of 6 hours at 0.7 bar of overpressure, a temperature of 28° C., an aeration of 5 l/minute and a stirring speed of 350 rpm, a solution of 1.0 g of 7α-methylestr-4-ene-3,17-dione in 15 ml DMF was added. Stirring was continued, and it was aerated. After 22 hours, the culture broth was harvested and extracted twice for 4 hours with 7 l of methyl isobutyl ketone. The combined organic phases were evaporated to the dry state. The residue was dissolved to a large extent in methanol. The silicone oil was filtered off. It was concentrated by evaporation, and after chromatography on silica gel with a gradient that consists of dichloromethane and acetone, 0.78 g (74%) of 11α-hydroxy-7α-methylestr-4-ene-3,17-dione was isolated. After recrystallization from acetone/diisopropyl ether, 311 mg (29.6%) of white crystals with a melting point of 200° C. and [α]D=+52° (CHCl3, c=0.5905) was isolated.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].[OH-].[Na+].Cl.CN(C)CCCN=C=NCC.Cl.[NH2:30][CH:31]1[C:44](=[O:45])[N:33]2[CH:34]([C:39]3[NH:43][N:42]=[N:41][N:40]=3)[C:35]([CH3:38])([CH3:37])[S:36][C@H:32]12.C(C(CCCC)C([O-])=O)C.[Na+]>C(OCC)(=O)C.O>[C:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:11][C:12]([NH:30][CH:31]1[C:44](=[O:45])[N:33]2[CH:34]([C:39]3[NH:40][N:41]=[N:42][N:43]=3)[C:35]([CH3:37])([CH3:38])[S:36][C@H:32]12)=[O:14])([OH:10])=[O:9]
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: O=C(O)Cc1ccccc1CC(=O)O
Agent: CCCCC(CC)C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3CC(=O)O)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.5 h

Procedure:
An ice-bath cooled, stirred mixture of 1.94 g (10 mmol) of o-phenylenediacetic acid, and 60 ml. of water is adjusted to pH 5.5 by the careful addition of 6N sodium hydroxide. The resulting solution is treated with 1.92 g (10 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and stirring is continued for 30 minutes, with the pH being maintained at 5.5 by the addition of 6.0N hydrochloric acid. A solution consisting of 2.4 g. (10 mmol) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 30 ml. of water (adjusted to pH 7) is added to the first mentioned solution and stirring and cooling is continued for an hour. The aqueous solution is washed three times with 30 ml. portions of ethyl acetate, and is then adjusted to pH 2.5 with 6N hydrochloric acid. This solution is extracted twice with 40 ml. portions of ethyl acetate, and the combined extracts are washed with 50 ml. of water. After being dried over anhydrous sodium sulfate, the extract is evaporated under reduced pressure to furnish a colorless foam: yield 3 g. The foam is dissolved in 50 ml. of ethyl acetate and then it is treated with 2.4 g. (14.5 mmol) of sodium 2-ethylhexanoate in 30 ml. of ethyl acetate. The title compound precipitates as the sodium salt: yield 3.4 g (74%) IR (KBr) 1770, 1667, and 1587 cm-1NMR (D2O): 7.25 ppm (s, 4H), 5.70 (d, 1H), 5.40 (d, 1H), 5.25 (s, 1H), 3.70 (s, 2H), 3.60 (s, 2H), 1.50 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][OH:6]
Reactant: C1CCOCC1
Reactant: OCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: OCCOCCOC1CCCCO1
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To 800 mL of CH2Cl2 were added diethylene glycol (57 mL, 0.6 mol) and p-toluenesulfonic acid monohydrate (5.7 g, 30 mmol) successively. Then tetrahydropyran (27.4 mL, 0.3 mol) was added dropwise at 0° C. The reaction mixture was stirred overnight and quenched with H2O, extracted with CH2Cl2, washed with H2O and brine successively, concentrated through rotary evaporation, and subjected to silica gel chromatography using CH2Cl2/MeOH as the eluent to afford compound 28 (32.5 g, 0.17 mol, 57% yield) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 4.59 (t, J=4.0 Hz, 1H), 3.85-3.80 (m, 2H), 3.68-3.64 (m, 4H), 3.59-3.55 (m, 3H), 3.48-3.44 (m, 1H), 2.98 (br, 1H), 1.81-1.76 (m, 1H), 1.71-1.65 (m, 1H), 1.59-1.46 (m, 4H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH2:13][CH2:12][CH2:11][N:10]3[CH:9]=1)=[O:7])C>C(O)C.O>[C:8]1([C:6]([OH:7])=[O:5])[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH2:13][CH2:12][CH2:11][N:10]3[CH:9]=1
Reactant: CCOC(=O)c1cn2c3c(cccc13)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c3c(cccc13)CCC2
Temperature: 22 °C
Yield: 82.4 %

Procedure:
Add 5 N aqueous sodium hydroxide (60 mL, 0.3 mol) to a solution of 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid ethyl ester (31 g, 0.14 mol) in ethanol (200 mL) and water (70 mL) and stir the resulting mixture at reflux for 3 hours. Cool the reaction mixture to 20-24° C., dilute with water (2 L), and wash sequentially with dichloromethane (2×200 mL) and diethyl ether (1×200 mL). Filter the aqueous layer through Celite and treat the filtrate with concentrated hydrochloric acid (25 mL) to precipitate the product. Filter the solid, wash with water (200 mL), and dry under reduced pressure to give the desired compound as a light yellow solid (23.2 g, 85%).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:12][C:13](=[O:15])[CH:14]=2)=[O:11])=[CH:5][CH:4]=1)#C.NC1C=CC=CC=1[OH:23].CC(C)=O.C(OC(=O)C)(=O)C>C([O-])(=O)C.[Ni+2].C([O-])(=O)C.C(N(CC)CC)C>[OH:23][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:12][C:13](=[O:15])[CH:14]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(C2=CC(=O)NC2=O)cc1
Reactant: Nc1ccccc1O
Agent: [Ni+2]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: O=C1C=C(c2ccc(O)cc2)C(=O)N1

Procedure:
4-hydroxyphenyl maleimide was prepared by the same procedure as for 4-ethynylphenyl maleimide with the following starting materials aminophenol (54.5 g, 0.50 mole) maleic anhydride (49.0 g, 0.50 mole), acetone (500 ml), triethylamine (11 ml), nickel (II) acetate (0.5 g, 43 mmol), and acetic anhydride (63.8 g, 0.625 mol).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:19])[C:9]2[C:17]3[C:16]([CH3:18])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)=[C:6]([F:20])[CH:5]=[CH:4][C:3]=1[NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[F:1][C:2]1[C:7]([C:8]([C:9]2[C:17]3[C:16]([CH3:18])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)=[O:19])=[C:6]([F:20])[CH:5]=[CH:4][C:3]=1[NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23]
Reactant: Cc1ncnc2[nH]cc(C(O)c3c(F)ccc(NS(=O)(=O)CC(C)C)c3F)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Product: Cc1ncnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)CC(C)C)c3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To 2-methyl-propane-1-sulfonic acid {2,4-difluoro-3-[hydroxy-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-phenyl}-amide (77, 99 mg, 0.24 mmol) in 2 mL of tetrahydrofuran, Dess-Martin periodinane (112 mg, 0.265 mmol) is added and the reaction is stirred at room temperature for 2 hours. The reaction is poured into saturated aqueous sodium thiosulfate along with some sodium bicarbonate solid and extracted with ethyl acetate. The organic layer is washed with water, then brine, and dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-1003, 28 mg). MS (ESI) [M+H+]+=409.3.