Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C.[OH:18][C@H:19]1[CH2:23][N:22]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[C@@H:21]([C:37]([OH:39])=O)[CH2:20]1.Cl.Cl.[N+:42]([C:45]1[CH:63]=[CH:62][C:48]([CH2:49][O:50][C:51]([O:53][CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[O:52])=[CH:47][CH:46]=1)([O-:44])=[O:43]>CN(C)C=O.C(OCC)(=O)C>[OH:18][C@H:19]1[CH2:23][N:22]([C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:25])[C@@H:21]([C:37]([N:59]2[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][O:53][C:51]([O:50][CH2:49][C:48]3[CH:62]=[CH:63][C:45]([N+:42]([O-:44])=[O:43])=[CH:46][CH:47]=3)=[O:52])[CH2:57][CH2:58]2)=[O:39])[CH2:20]1
Reactant: O=C(OCCN1CCNCC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCCN1CCN(C(=O)[C@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
3.34 ml of diethyl cyanophosphate and 8.92 ml of triethylamine were added, whilst ice-cooling, to a suspension of 6.2 g of cis-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-D-proline and 8.41 g of 1-[2-(4-nitrobenzyloxycarbonyloxy)ethyl]piperazine dihydrochloride in 62 ml of dry dimethylformamide, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, the reaction mixture was diluted with 250 ml of ethyl acetate, and the dilute solution was washed with water and then dried over anhydrous magnesium sulfate. The mixture was concentrated by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 7.84 g of the title compound, as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH:11]([CH3:13])[CH3:12].C[Al](C)C.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[CH2:10]([N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:3]1[CH:4]=[CH:5][C:6]([N:8]2[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]2[CH3:25])=[CH:7][C:2]=1[F:1])[CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)CN(CC(C)C)c1ccc(N)cc1F
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N(CC(C)C)CC(C)C)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of 2-fluoro-N1,N1-diisobutylbenzene-1,4-diamine (0.40 g, 1.68 mmol) in CH2Cl2 (20 mL) was added trimethylaluminum (8.4 mL, 8.4 mmol, 1 M in heptane) slowly at rt. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (290 mg, 1.85 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred at rt for 3 days, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as pale yellow oil (280 mg, 48%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1ccc(O)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1ccc(O)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 4-aminophenol (56.0 mg, 0.51 mmol). The title compound was obtained as a solid (10 mg, 5% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.34 (1H, s), 9.36 (1H, m), 9.00 (2H, s), 8.66 (1H, m), 7.42 (2H, m), 6.74 (2H, m). MS m/z: 440.14, 442.17 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]([N:9]=[C:10]=[O:11])=[O:8])=[O:5])[CH3:2].[C:12]([CH:14]1[CH2:16][NH:15]1)#[N:13]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH2:6][C:7]([NH:9][C:10]([N:15]1[CH2:16][CH:14]1[C:12]#[N:13])=[O:11])=[O:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)CC(=O)N=C=O
Reactant: N#CC1CN1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)NC(=O)N1CC1C#N
Reaction time: 0.08 h

Procedure:
4 g. Ethoxycarbonylacetyl isocyanate are dissolved in 40 ml. toluene and mixed, while stirring, at 20°-30° C. with a solution of 1.73 g. 2-cyanoaziridine in 20 ml. toluene. After about 5 minutes, an oily deposit separates out which, after trituration, gradually solidifies. The suspension thus obtained is further stirred for 1 hour at ambient temperature, then filtered off with suction and washed with toluene and the solid product triturated with anhydrous diethyl ether. There are thus obtained 3.7 g. 1-(N-ethoxycarbonylacetyl-carbamoyl)-2-cyanoaziridine; m.p. 121°-123° C. The product is practically insoluble in water but is soluble in dilute aqueous sodium hydroxide solution.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].F[C:7]1[CH:17]=[C:16]([NH:18][CH3:19])[C:15]([N+:20]([O-:22])=[O:21])=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[H-].[Na+].C(O)(C(F)(F)F)=O>C1COCC1.CN(C=O)C>[F:1][CH:2]([F:5])[CH2:3][O:4][C:7]1[CH:17]=[C:16]([NH:18][CH3:19])[C:15]([N+:20]([O-:22])=[O:21])=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1F
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1OCC(F)F
Temperature: 25 °C

Procedure:
A solution of 2,2-difluoroethanol (1.7 g; 20.6 mmol) in THF (50 mL) was added to a solution of ethyl 2-fluoro-4-(methylamino)-5-nitrobenzoate (5.0 g; 20.6 mmol) in DMF (100 mL). Sodium hydride (0.824 g; 60%; 20.6 mmol) was added in portions and the mixture was stirred over night at rt. A solution of TFA (30 mL; 0.45 M aq) was added and the mixture was concentrated. The resulting precipitation was filtered off, washed with water, dried and recrystallized from EtOH/water to give the sub-title compound. Yield: 4.8 g (76%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[C:23]([N:24]=[C:25]=[S:26])=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C=O)C.O.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:25]2[S:26][C:18]3[C:23]([N:24]=2)=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=C=Nc1cccnc1Cl
Reactant: Nc1ncc(Br)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnc(Nc2nc3cccnc3s2)c(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3-(Benzyloxy)-5-bromopyridin-2-amine (10.0 g, 35.83 mmol) was added to a mixture of 2-chloro-3-isothiocyanatopyridine (6.112 g, 35.83 mmol) in DMF. The reaction was stirred at 80° C. for an hour, then at 110° C. for two hours. The reaction was cooled, diluted in water (200 mL) and 2N NaOH (35 mL), stirred for 30 minutes, and then filtered. The wet solids were washed with water, then dissolved in dichloromethane (300 mL) dried over MgSO4, and filtered. Hexane (300 mL) was added to the combined filtrates, the mixture was concentrated to 500 mL, and then mixture stirred for 30 minutes. The mixture was filtered to afford the first crop of the title compound. The mother liquor was concentrated to 500 mL (until most of the dichloromethane was removed), filtered, washed with hexanes to afford a second crop of the title compound. The two crops combined afforded the title compound (10.2 g, 68.7%) as light yellow crystals: 1H NMR (CDCl3) δ 5.14 (s, 2H), 7.30-7.33 (m, 2H), 7.42-7.48 (m, 5H), 7.87 (d, 1H), 8.10 (s, 1H), 8.40 (d, 1H), 8.67 (bs, 1H).
Reaction SMILES: [Cl:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][C@H:15]([CH3:29])[C@:16]2([O:24][C:25](=[O:28])[CH2:26][CH3:27])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:31])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:30])[CH:6]=[CH:5]1.[C:32](OC(=O)C)(=[O:34])[CH3:33].O.Cl>N1C=CC=CC=1>[C:32]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([O:24][C:25](=[O:28])[CH2:26][CH3:27])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([Cl:1])[CH2:22]2)[C@:4]2([CH3:31])[C:9](=[CH:8][C:7](=[O:30])[CH:6]=[CH:5]2)[CH2:10][CH2:11]3)[CH2:14][C@@H:15]1[CH3:29])(=[O:34])[CH3:33]
Reactant: CCC(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)O[C@]1(C(=O)COC(C)=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C

Procedure:
A solution of 11β-chloro-21-hydroxy-16β-methyl-17-propionyloxypregna-1,4-diene-3,20-dione (75 mg) in pyridine (1 ml) was treated with acetic anhydride (0.2 ml) at room temperature. After 3 hours water (0.4 ml) was added and the solution was poured into dilute by hydrochloric acid. The precipitated solid was removed by filtration and after drying was recrystallized from methanol to give the title compound, m.p. 212°-213°(K), [α]D + 101.1° (c 0.6 chloroform). λmax 239 nm (ε 16,280) (Found: C, 65.7; H, 7.0; Cl, 6.8. C27H35ClO6 requires C, 66.0; H, 7.2, Cl, 7.2%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C@@H:7]2[CH2:11][C@H:10]([S:12][C:13]3[CH2:19][C@H:18]4[N:15]([C:16](=[O:36])[C@@H:17]4[C@H:20]([O:22]C(OCC4C=CC([N+]([O-])=O)=CC=4)=O)[CH3:21])[C:14]=3[C:37]([O:39]CC3C=CC([N+]([O-])=O)=CC=3)=[O:38])[CH2:9][N:8]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[N:6]=1.P([O-])([O-])([O-])=O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C@@H:7]2[CH2:11][C@H:10]([S:12][C:13]3[CH2:19][C@H:18]4[N:15]([C:16](=[O:36])[C@@H:17]4[C@H:20]([OH:22])[CH3:21])[C:14]=3[C:37]([OH:39])=[O:38])[CH2:9][NH:8]2)[N:6]=1
Reactant: [H][H]
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](c4csc(N)n4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](c4csc(N)n4)C3)C[C@H]12
Yield: 65.5 %

Procedure:
A mixture of 4-nitrobenzyl (5R,6S)-3-[(2S,4S)-2-(2-aminothiazol-4-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.85 g), 20% palladium hydroxide on carbon (500 mg), 0.05 M phosphate buffer (pH 6.5, 30 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 4 hours under atmospheric pressure of hydrogen. After the catalyst was filtered off, the filtrate was concentrated to remove the organic solvent. The residue was washed with ethyl acetate, adjusted to pH 6.2 with aqueous potassium carbonate and concentrated to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (60 ml) eluting in turn with water (300 ml) and 5% aqueous acetone (200 ml). The fractions containing the desired compound were collected and lyophilized to give (5R, 6S)-3-[(2S,4S)-2-(2-aminothiazol-4-yl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-7-oxo-1azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (540 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[C:5]([CH3:8])=[N:6][CH:7]=1.C([O-])(=O)C.[K+].CC([N+:22]([O-])=O)(C)C.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10](=[O:12])[CH3:11])[N:22]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: CC(=O)Nc1cc(Br)cnc1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)n1ncc2ncc(Br)cc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
A solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (2.8 g, 12 mmol) and potassium acetate (3.59 g, 36.6 mmol) in toluene (50 mL) was heated at 80° C. under nitrogen. After 30 min, 2-methyl-2-nitropropane (3.77 g, 36.6 mmol) and acetic anhydride (3.73 g, 36.6 mmol) were added, and the resulting mixture was stirred at 80° C. for another 18 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (50 mL). The aqueous mixture was extracted with ethyl acetate (3×60 mL). The collected organic extractions were concentrated in vacuo. Purification by flash column chromatography (5→10% ethyl acetate in petroleum ether) afforded 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethanone (1.4 g, 48.% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.90 (s, 1 H), 8.75 (s, 1 H), 8.32 (s, 1 H), 2.79 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][C@@H:9]1[CH3:21])([CH3:4])([CH3:3])[CH3:2].O([CH2:31][C:32]([F:35])([F:34])[F:33])S(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][C@@H:9]1[CH3:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: C[C@H]1Oc2ccc(F)cc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H]1Oc2ccc(F)cc2N(CC(F)(F)F)C(=O)[C@H]1NC(=O)OC(C)(C)C
Reaction time: 5 h
Yield: 87.1 %

Procedure:
To a solution of 0.50 g (1.61 mmol) ((6R,7S)-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester in 5 ml dimethylformamide were added at room temperature 0.57 g (2.42 mmol) 2,2,2-trifluorethyl triflate and 0.80 g (2.43 mmol) cesium carbonate. Stirring was continued for 5 hours. Extraction with ethylacetate/water and chromatography on silicagel with heptane to ethylacetate/heptane 2:8 yielded 0.55 g (87%) [(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester, MS m/e (%): 415.3 (M+Na+, 100), 393.2 (M+H+, 8), 293.1 (43).
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:39])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[CH:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([O:33]C)=[C:29]([O:35]C)[C:28]=3[O:37]C)[CH:24]=[CH:25][CH:26]=2)=[O:20])=[CH:10][CH:11]=1.B(Br)(Br)Br.O>C(Cl)Cl.CO>[OH:37][C:28]1[C:29]([OH:35])=[C:30]([OH:33])[CH:31]=[CH:32][C:27]=1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:9]2[S:8][C:7]([CH2:6][C:5]([OH:39])=[O:4])=[CH:11][CH:10]=2)=[O:20])[CH:22]=1.[CH3:3][O:4][C:5](=[O:39])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[CH:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([OH:35])[C:28]=3[OH:37])[CH:24]=[CH:25][CH:26]=2)=[O:20])=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1ccc(-c2ccccc2NC(=O)c2cccc(-c3ccc(OC)c(OC)c3OC)c2)s1
Agent: BrB(Br)Br
Agent: N#N
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1ccc(-c2ccccc2NC(=O)c2cccc(-c3ccc(O)c(O)c3O)c2)s1
Product: O=C(O)Cc1ccc(-c2ccccc2NC(=O)c2cccc(-c3ccc(O)c(O)c3O)c2)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 23 %
Yield: 13 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve (5-{2-[(2′,3′,4′-Trimethoxy-biphenyl-3-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid methyl ester (47) (66 mg, 0.13 mmol) in anhydrous DCM (3.4 mL) at −78° C., add dropwise a 1M solution of BBr3 in DCM (1.05 mL, 1.05 mmol) and stir for additional 30 min at −78° C. After slowly warming up stir the reaction solution for additional 4 h at rt. Cool reaction mixture to 0° C., add dropwise water and DCM under vigorous stirring followed by MeOH to homogenize the mixture. Partition the hydrolized reaction mixture between water and EtOAc, extract the aqu. layer with EtOAc (3×), wash combined organic layer with brine and dry it with Na2SO4. Purify the crude product by preparative RP HPLC (gradient, water/CH3CN 95:5 to 5:95) to obtain (5-{2-[(2′,3′,4′-Trihydroxy-biphenyl-3-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid (48) (8 mg, 13%) as a white solid and (5-{2-[(2′,3′,4′-Trihydroxy-biphenyl-3-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid methyl ester (49) (14 mg, 23%) as a brown foam. 1H NMR (400 MHz, CD3OD) (48): 3.86 (s, 2H); 6.49 (d, 1H, J=8.6 Hz); 6.74 (d, 1H, J=8.6 Hz); 6.98 (d, 1H, J=3.0 Hz); 7.19 (d, 1H, J=3.3 Hz); 7.36 (t, 1H, J=7.6 Hz); 7.43 (t, 1H, J=7.6 Hz); 7.51 (t, 1H, J=7.8 Hz); 7.62 (d, 1H, J=7.8 Hz); 7.71-7.84 (m, 3 Hz); 8.08 (br.s 1H); (49): 3.66 (s, 3H); 3.88 (s, 2H); 6.49 (d, 1H, J=8.3 Hz); 6.74 (d, 1H, J=8.3 Hz); 6.97 (d, 1H, J=3.5 Hz); 7.19 (d, 1H, J=3.5 Hz); 7.36 (td, 1H, J1=7.6 Hz, J2=1.5 Hz); 7.43 (td, 1H, J1=7.6 Hz, J2=1.5 Hz); 7.51 (t, 1H, J=7.8 Hz); 7.62 (dd, 1H, J1=7.6 Hz, J2=1.5 Hz); 7.73 (d, 1H, J=7.8 Hz); 7.81 (Ψdd, 2H, J1=7.6 Hz, J2=1.5 Hz); 8.09 (br.s 1H).
Reaction SMILES: [OH:1][C@@H:2]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([NH:27][C@@H:28]([CH3:33])[C:29]([O:31]C)=[O:30])=[O:26])[CH:6]=1)[CH2:3][OH:4].O[Li].O>C1COCC1.O>[OH:1][C@@H:2]([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[N:8]=[C:7]([C:25]([NH:27][C@@H:28]([CH3:33])[C:29]([OH:31])=[O:30])=[O:26])[CH:6]=1)[CH2:3][OH:4]
Reactant: COC(=O)[C@H](C)NC(=O)c1cc([C@H](O)CO)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1cc([C@H](O)CO)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(=O)O

Procedure:
To a solution of (S)-methyl 2-(6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamido)propanoate (0.100 g, 0.22 mmol) in 5:1 THF/water (5 mL) was added LiOH.H2O (0.009 g, 0.21 mmol). After stirring overnight additional LiOH.H2O (0.001 g, 0.02 mmol) was added. After 5 hours the reaction was evaporated in vacuo. To the residue was added 5 mL water and 0.22 mL 1N HCl. The resulting precipitate was filtered off, washed with water, and dried under vacuum. The solid was triturated with 2 mL 20% EtOAc/hexanes, isolated, and rinsed with additional hexanes. The material was dried under vacuum to give (S)-2-(6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamido) propanoic acid (Compound Example No. 15) as an off-white powder (0.062 g, 0.14 mmol, 64% yield). 1H NMR (400 MHz, DMSO-d6): 12.82 (1 H, s), 9.23 (1 H, d, J=7.9 Hz), 8.62 (2 H, d, J=9.0 Hz), 8.00 (1 H, s), 7.33-7.25 (2 H, m), 7.23-7.16 (2 H, m), 7.13 (2 H, d, J=8.8 Hz), 5.82 (1 H, d, J=5.3 Hz), 4.83 (1 H, t, J=5.9 Hz), 4.70 (1 H, q, J=4.4 Hz), 4.55 (1 H, p, J=7.5 Hz), 3.84-3.76 (1 H, m), 3.71-3.63 (1 H, m), 1.48 (3 H, d, J=7.2 Hz); LC/MS: m/z=442.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:4]([SH:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:4]([S:11][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: BrCc1ccccc1
Reactant: COc1ccc(Oc2c(N)cc(C(=O)O)cc2S)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(Oc2c(N)cc(C(=O)O)cc2SCc2ccccc2)cc1
Reaction time: 17 h

Procedure:
5-Amino-4-(p-methoxyphenoxy)-3-mercaptobenzoic acid (2 g) is dissolved in 1 N sodium hydrogen carbonate (50 ml), and after addition of benzyl bromide (0.85 ml), the reaction mixture is stirred for 17 hours. After extraction twice with diethyl ether (25 ml), the aqueous layer is adjusted to pH 2 by addition of 4 N hydrochloric acid. The precipitated 5-amino-3-benzylthio-4-(p-methoxyphenoxy)-benzoic acid is collected and recrystallized from aqueous ethanol. After drying in vacuo at 80° C, the compound is obtained with a melting point of 158°-161° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][S:14][C:12]=2[N:13]=1.S(Cl)([Cl:20])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Cl:20][C:10]1[C:11]2[CH:16]=[CH:15][S:14][C:12]=2[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=1
Reactant: O=c1[nH]c(-c2ccccc2F)nc2sccc12
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1nc(Cl)c2ccsc2n1
Yield: 45 %

Procedure:
2-(2-Fluoro-phenyl)-3H-thieno[2,3-d]pyrimidin-4-one (900 mg, 3.65 mmole) was dissolved in chloroform and thionyl chloride (0.532 ml, 7.30 mmole) was added to the mixture followed by 1 ml dimethylformamide. The reaction mixture was heated to reflux for 2.5 hours, the cooled mixture was washed with 10% sodium carbonate, the chloroform solution was dried over sodium sulfate (anh) and the solvent was removed. The crude product was chromatographed on silica gel, eluting with chloroform. Upon removal of solvent 438 mg of product was obtained (yield: 45%).
Reaction SMILES: [CH2:1]([P:4](=[O:10])([CH2:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH2:2][CH3:3].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>CCOCC>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:6][CH2:5][P:4]([CH2:7][CH2:8][CH3:9])([CH2:1][CH2:2][CH3:3])=[O:10])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CCCP(=O)(CO)CCC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCP(=O)(CCC)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
To dipropyl hydroxymethylphosphine-oxide (Ref. U.S. Pat. No. 5,272,128) (16.4 g, 0.1 mol) in anhydrous ether (200 mL) at 0° C., was added p-toluenesulfonyl chloride (19.1 g, 0.1 mol), triethyl amine (27.8 mL, 0.2 mol). The reaction was stirred at room temperature over night. The ether solution was decanted, and the precipitate was washed in a filter funnel with ˜1 L ether until HPLC found no product. Combined ether layer were concentrated. The crude product was purified on silica gel chromatography with 8% MeOH/DCM.