Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][C:10]2[CH:24]=[CH:23][C:13]([O:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][C:15]([CH3:21])([CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:23][CH:24]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C=Nc2ccc(Cl)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1ccc(CNc2ccc(Cl)cc2)cc1
Product: Cl
Reaction time: 1 h
Yield: 132.4 %

Procedure:
In 40 ml of methanol is dissolved 5.3 g of ethyl 2-[4-{N-(4-chlorophenyl)formimidoyl}phenoxy]-2-methylpropionate. Over a period of about 1 hour, 0.58 g of sodium borohydride is added to the solution at 20° to 25° C. with stirring. After stirring the mixture at room temperature for 1 hour, the methanol is distilled off, and the residual oil is dissolved in ether. The solution is washed with water and dried, and the ether is thereafter distilled off. The resulting oily residue (4.2 g) is dissolved in 20 ml of ether. A mixture of hydrochloric acid and ethanol is added to the solution. The resulting precipitate is collected by filtration and washed with ether to give 3.9 g of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionate hydrochloride, mp 139° to 141° C. Recrystallization of the crystals from a mixture of methanol and ether gives 3.1 g of crystals, mp 143° to 145° C. The crystals are suspended in a mixture of ether and water, and the suspension is adjusted to pH 8 to 9 by addition of 28% ammonia water. The ether layer is thereafter separated, washed with water and dried. After drying, removal of the ether by distillation gives 2.9 g of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionate as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][CH:17]([O:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:19]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(OC(=O)c3ccccc3)CC2)CC1

Procedure:
In analogy to the procedures described for intermediates 3B, 3C, 1, 4B and for example 1, the title compound has been prepared by the following reaction sequence: i) 4-hydroxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester [Lawrence, L.; Rigby, A.; Sanganee, H.; Springthorpe, B. PCT Int. Appl. (2001), WO 2001077101 A1] was reacted with benzoyl chloride to give 4-benzoyloxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester; ii) 4-benzoyloxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester was reacted with trifluoroacetic acid to give benzoic acid [1,4′]bipiperidinyl-4-yl ester; iii) 4-bromo-2,6-dimethyl-benzoic acid was converted into its acid chloride and reacted with benzoic acid [1,4′]bipiperidinyl-4-yl ester to give benzoic acid 1′-(4-bromo-2,6-dimethyl-benzoyl)-[1,4′]bipiperidinyl-4-yl ester; iv) benzoic acid 1′-(4-bromo-2,6-dimethyl-benzoyl)-[1,4′]bipiperidinyl-4-yl ester was saponified to give (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone; v) Suzuki reaction of (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone with 3-trifluoromethyl-phenyl boronic acid gave the title compound as light brown solid. MS: 461.3 (MH+).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[S:21](Cl)(=[O:23])=[O:22]>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:21]([C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[CH3:11])(=[O:22])=[O:23])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc([N+](=O)[O-])ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Orcinol monohydrate (2.84 g, 20.0 mmol) and 2-methyl-5-nitrobenzenesulfonyl chloride (4.71 g, 20.0 mmol) were mixed in saturated aqueous NaHCO3 (60 mL) and diethyl ether (60 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (100 mL) and extracted into ethyl acetate (3×60 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow solid (4.20 g, 72%). 1H-NMR (300 MHz, CDCl3) δ 8.71 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 6.56 (s, 1H), 6.44 (s, 1H), 6.33 (s, 1H), 5.42 (s, 1H), 2.91 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[OH:5][C:6]1[CH:16]=[CH:15][CH:14]=[C:8]2[C:9]([O:11][C:12](=[O:13])[C:7]=12)=O.[N+](C1C=CC=CC=1)([O-])=O.[C:26]([C:29]1[O:30][C:31](C)=[CH:32][CH:33]=1)(=O)C>>[OH:5][C:6]1[CH:16]=[CH:15][CH:14]=[C:8]2[C:7]=1[C:12](=[O:13])[C:31]1[O:30][C:29]([CH3:26])=[CH:33][C:32]=1[C:9]2=[O:11]
Reactant: O=C1OC(=O)c2c(O)cccc21
Reactant: CC(=O)c1ccc(C)o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cc2c(o1)C(=O)c1c(O)cccc1C2=O
Temperature: 100 °C

Procedure:
Aluminum chloride (2.5 g) and 3-hydroxyphthalic anhydride (1 g) were added to nitrobenzene (5 ml), to which was added 2-acetyl-5-methylfuran (0.7 g), dropwise, and heated at 100° C. overnight.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)=[N+:2]=[N-:3].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.C(OC(=O)C)(=O)C>O1CCOCC1>[N:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[C:10](=[O:11])[C:5]=12)=[O:9])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cccc2c1C(=O)OC2=O
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(c1ccc(C(=O)O)cc1)C2=O
Temperature: 85 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
A solution of 3.78 g (0.02 mol) of 3-azidophthalic anhydride in 50 ml of dioxan is mixed with a solution of 2.74 g (0.02 mol) of p-aminobenzoic acid in 50 ml of dioxan and the mixture is left to stand for 3 hours. 5 ml of acetic anhydride are then added and the reaction mixture is heated for 1 hour at 85° C. After concentrating to dryness, the residue is mixed with water and the resulting crystals are filtered off with suction. 4.8 g (78% of theory) of 4-(3-azidophthalimidyl)-benzoic acid are obtained; melting point 300° C. (with decomposition).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH:4]=[CH:3][O:2]1.[C:7]1(=[O:14])[O:11][CH2:10][CH:9]([CH:12]=C)[O:8]1.FC1C=CC=CC=1>>[C:1]1(=[O:6])[O:5][CH2:4][CH2:3][O:2]1.[C:7](=[O:14])([O:8][CH2:9][CH3:12])[O:11][CH3:10]
Reactant: C=CC1COC(=O)O1
Reactant: O=c1occo1
Solvent: Fc1ccccc1
Product: CCOC(=O)OC
Product: O=C1OCCO1

Procedure:
A mixed solvent of ethylene carbonate and methyl ethyl carbonate was prepared at a capacity ratio of 10:30. To the mixed solvent, 2% by weight of vinylene carbonate, 2% by weight of vinylethylene carbonate, 5% by weight of fluorobenzene, and 5% by weight of phosphazene were added, obtaining a mixed solution. LiPF6 was dissolved in this mixed solution at a concentration of 1.5 mol/L, obtaining a non-aqueous electrolyte.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])([O-])=O.[Zn+2:9].[N+]([O-])([O-])=O.[P:14](=[O:18])([OH:17])([OH:16])[OH:15]>O>[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Zn+2:9].[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Zn+2:9].[Zn+2:9]
Reactant: O=P(O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [Zn+2]
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=P([O-])([O-])[O-]

Procedure:
a phosphatizing solution based on: zinc phosphate diacid, nitric acid, zinc nitrate and phosphoric acid, diluted in water at 5 to 20%, at a temperature of 60 to 85° C. for a time which can vary between 5 and 15 minutes, to produce a zinc phosphate coating which is compact and uniform and has a very fine crystalline structure in order to facilitate the mechanical deformation of the material when cold;
Reaction SMILES: [CH:1]1([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:13][C:12]=2[F:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Sm].II.Cl>O.CO.O1CCCC1>[CH:1]1([O:10][C:11]2[C:12]([F:24])=[CH:13][C:14]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:16]=2[F:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)/C=C/c1cc(F)c(OC2CCc3ccccc32)c(F)c1
Agent: Cl
Agent: II
Agent: [Sm]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)CCc1cc(F)c(OC2CCc3ccccc32)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a mixture of methyl (E)-3-[4-[(2,3-dihydro-1H-inden-1-yl)oxy]-3,5-difluorophenyl]-2-propenoate (0.52 g, 1.6 mmol), samarium (1.2 g, 7.9 mmol), tetrahydrofuran (3 mL) and methanol (7 mL) was added iodine (0.80 g, 3.2 mmol), and the reaction mixture was stirred at room temperature overnight. 1 N Hydrochloric acid (20 mL) was added thereto, and the mixture was stirred for 20 minutes, then diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=10:1) to give the title compound. Yield 60%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH:33][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: COc1ccccc1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1CNC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 115.2 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), o-methoxybenzylamine (21.8 μL, 0.17 mmol), triethylamine (58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 46 mg (81%) of the title compound as a TFA salt (1.5 H2O, 1.5 TFA, effective MW=673.59). 1H NMR (DMSO-d6): δ 9.83 (1H, s), 9.03 (1H, t, J=3.4), 8.70 (1H, d, J=3.7), 8.08 (4H, m), 7.82 (1H, d, J=7.4), 7.49 (4H, m), 7.21 (3H, m), 6.96 (4H, m), 4.48 (2H, d, J=6.3). ESIMS (M+H+): 476.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:25]2[C:20](=[N:21][C:22]([S:27][CH3:28])=[N:23][C:24]=2[NH2:26])[NH:19][N:18]=1.C(NC(C)C)(C)C>S(Cl)(Cl)=O.O1CCCC1>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:25]2[C:20](=[N:21][C:22]([S:27][CH3:28])=[N:23][C:24]=2[NH:26][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[NH:19][N:18]=1
Reactant: O=C(O)c1ccccn1
Reactant: CSc1nc(N)c2c(-c3ccccc3Cl)n[nH]c2n1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CC(C)NC(C)C
Product: CSc1nc(NC(=O)c2ccccn2)c2c(-c3ccccc3Cl)n[nH]c2n1
Temperature: 25 °C

Procedure:
Pyridine-2-carboxylic acid (78 mg, 0.64 mmol) was placed in 5 ml thionyl chloride and refluxed for 3 hours. Excess thionyl chloride was then removed in vacuo and the crude acid chloride was suspended in 2 ml anhydrous tetrahydrofuran. The solution of acid chloride was added to a mixture of 3-(2-chloro-phenyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (190 mg, 0.64 mmol) and diisopropylamine (247 mg, 1.92 mmol) in 6 ml anhydrous tetrahydrofuran. The reaction mixture was refluxed for 15 h. After cooling to room temperature the resulting mixture was partition between 60 ml ethylacetate and 15 ml brine. The organic layer was washed 3 times with 3N HCl, next with saturated sodium bicarbonate solution and brine. After drying with sodium sulfate and solvent evaporation in vacuo, 140 mg of pyridine-2-carboxylic acid [3-(2-chloro-phenyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amide, MS: 397.1 (M+H), was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:12]([CH2:15][C:16](OC)=O)(=[O:14])=[O:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(N(CC)C(C)C)(C)C.FC(F)COS([C:36]([F:39])([F:38])F)(=O)=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([C:3]([O:2][CH3:1])=[O:4])[S:12]([CH2:15][CH2:16][CH:36]([F:38])[F:39])(=[O:13])=[O:14])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)CS(=O)(=O)Nc1nccnc1C(=O)OC
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nccnc1N(C(=O)OC)S(=O)(=O)CCC(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 110.7 %

Procedure:
To a solution of 3-methoxycarbonylmethanesulfonylamino-pyrazine-2-carboxylic acid methyl ester (Example 9.1) (1.212 g) in acetonitrile (12 ml) was added N,N-diisopropylethylamine (“Hunig's base”) (0.8 ml) at ambient temperature. The mixture was stirred at ambient temperature for 5 minutes before dropwise addition of a solution of 2,2-difluoroethyltrifluoromethanesulfonate (0.978 g) in acetonitrile (5 ml) at ambient temperature. The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate (30 ml) and aqueous sulfuric acid (2M) (30 ml). The phases were separated and the organic layer was concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:2) to give 3-[(2,2-difluoro-ethyl)-methoxycarbonyl-methanesulfonyl-amino]-pyrazine-2-carboxylic acid methyl ester (0.819 g). 1H-NMR (400 MHz, CDCl3): 8.70 (d, 1H), 8.65 (d, 1H), 6.06-6.29 (m, 1H), 4.32-4.38 (m, 2H), 4.18 (s, 2H), 4.02 (s, 3H), 3.78 (s, 3H) ppm.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([NH:18][C:19]4[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=4[C:21]([OH:23])=O)=[O:17])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.CN.C1COCC1.O[N:36]1[C:40]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:40][NH:36][C:21]([C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:16]([C:13]1[CH:12]=[CH:11][C:10]2[CH:9]=[C:8]3[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]3[C:15]=2[CH:14]=1)=[O:17])=[O:23]
Reactant: O=C(Nc1ccccc1C(=O)O)c1ccc2cc3n(c2c1)CCCNC3=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccccc1NC(=O)c1ccc2cc3n(c2c1)CCCNC3=O
Reaction time: 0.17 h
Yield: 106.3 %

Procedure:
To a solution of 2-{[(1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-8-yl)carbonyl]amino}benzoic acid (100 mg, 0.28 mmol) in DMF (1.0 mL) are added 2M methylamine in THF (0.69 mL, 1.38 mmol), N-hydroxybenzotriazole (26 mg, 0.20 mmol), N,N-diisopropylethylamine (0.10 mL, 0.55 mmol) and 4-dimethylaminopyridine (6.7 mg, 0.06 mmol). After the reaction mixture is stirred for 10 min, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (158 mg, 0.83 mmol) is added. The reaction mixture is then stirred for another 16 h at room temperature. The crude reaction mixture is purified by preparative HPLC using 10-85% acetonitrile/water with 0.1% TFA to afford the title compound (80 mg, 77%). LCMS (ESMS): m/z 377.20 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:16]2[O:15][C:14]([C:12]([NH:11][C:7]3[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:20])[CH:10]=[CH:9][CH:8]=3)=[O:13])=[CH:18][CH:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: O=C(O)Cc1cccc(NC(=O)c2ccc(-c3cccc(F)c3)o2)c1

Procedure:
The furyl bromide (16)(100 mg, 0.30 mmol) was coupled to 3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E. During this reaction, hydrolysis occurred. The residue was extracted using Work-up E1 to give the title compound. Yield: 26 mg, 25%; LC/MS tr 1.45 min; MS(ES+) m/z 339 (M+H); HPLC Purity: 91%; 1H NMR (400 MHz; DMSO): δ 3.50 (s, 2H), 6.95 (d, 1H), 7.15 (t, 1H), 7.20 (d, 1H), 7.24 (t, 1H), 7.32 (d, 1H), 7.46 (q, 1H), 7.56 (s, 1H), 7.62 (d, 1H), 7.74 (d, 1H), 7.83 (d, 1H), 10.13 (s, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:14])[CH:10]=[CH:9][C:8]=1[OH:27])[CH3:2].[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:14])[CH:10]=[CH:9][C:8]=1[O:27][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][Br:29])[CH3:2]
Reactant: CCOC(=O)CCc1cc(C(=O)c2ccccc2CC(=O)OCC)ccc1O
Reactant: BrCCCCCBr
Product: CCOC(=O)CCc1cc(C(=O)c2ccccc2CC(=O)OCC)ccc1OCCCCCBr
Yield: 74 %

Procedure:
Starting with 0.436 g (1.13 mmol) of 5-[[2-(2-ethoxy-2-oxoethyl)phenyl]carbonyl]-2-hydroxybenzenepropanoic acid ethyl ester, and 6.80 g (29.57 mmol) of 1,5-dibromopentane, the title compound was obtained as a pale yellow oil, in 74% yield, using the procedure of example 21.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:11])[C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7])(=[O:3])[CH3:2].C.[O:13]1[CH2:18]COC[CH2:14]1>>[N-:7]=[C:18]=[O:13].[CH3:14][O:9][C:8](=[O:10])[C@H:6]([C@@H:5]([CH3:11])[O:4][C:1](=[O:3])[CH3:2])[NH2:7]
Reactant: CC(=O)O[C@H](C)[C@H](N)C(=O)O
Reactant: C1COCCO1
Product: COC(=O)[C@@H](N)[C@@H](C)OC(C)=O
Product: [N-]=C=O

Procedure:
0.35 mol disphogene is added dropwise over 1 hour to a mixture of 0.28 mol of the methyl ester of O-acetylthreonine and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the filtrate is fractionally distilled to give O-acetylthreonine methyl ester isocyanate.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].CN(C)C=O.[OH:19][C@@H:20]1[CH2:24][NH:23][C:22](=[O:25])[CH2:21]1>O>[Si:10]([O:19][C@@H:20]1[CH2:24][NH:23][C:22](=[O:25])[CH2:21]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@H](O)CN1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.02 g of imidazole and 1.58 g of t-butyldimethylchlorosilane were added to a dimethylformamide (5 ml) solution of 1.01 g of (S)-4-hydroxy-2-pyrrolidone, and stirred overnight at room temperature. Water was added to the reaction liquid, and stirred with cooling with ice.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[NH:3]1.[Se](=O)=O.OO>CO>[OH:7][C:5]1[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[N:3]=[C:2]([CH3:1])[C:6]=1[C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=2)[C:5]=1[OH:7]
Reactant: CC1CC(=O)N(c2ccc(C(=O)O)cc2)N1
Agent: O=[Se]=O
Agent: OO
Solvent: CO
Product: Cc1nn(-c2ccc(C(=O)O)cc2)c(O)c1-c1c(C)nn(-c2ccc(C(=O)O)cc2)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.1 %

Procedure:
1 g of 3-methyl-1-(4-carboxyphenyl)-5-pyrazolidone (4.5 mmol) was dissolved in 20 ml of methanol and a sufficient amount of nitrogen gas was injected into the solution to replace the air with nitrogen. A catalytic amount of selenium dioxide (25 mg, 0.05 equivalent, MW 110.96) was added and 1.5 ml (3 equivalent) 30% hydrogen peroxide was added dropwise over an ice-cooled water bath. The mixture was stirred until room temperature. The stirring was continued for a further 12 hours while heating at 70-80° C. The deposited crystals were separated by filtration and dried under reduced pressure to obtain 460 mg of 5,5'-dihydroxy-3,3'-dimethyl-1,1'-bis(4-carboxyphenyl)-4,4'-bipyrazole (MW 434.12, 1.06 mmol, 47.1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)(=[O:10])=[O:9].[C:21](#[N:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].ICC#N>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[C:15]([O:20][CH2:22][C:21]#[N:23])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)(=[O:9])=[O:10]
Reactant: CC#N
Reactant: O=S(=O)(c1ccccc1F)n1ccc2c(O)cccc21
Agent: N#CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: N#CCOc1cccc2c1ccn2S(=O)(=O)c1ccccc1F
Temperature: 0 °C
Yield: 77 %

Procedure:
A 50 mL round-bottomed flask equipped with a magnetic stirrer was charged with 1-(2-fluorobenzenesulfonyl)-4-hydroxy-1H-indole (0.600 g, 0.002 mol), 25 mL of anhydrous acetonitrile and potassium carbonate (1.104 g, 0.008 mol). The reaction mixture was cooled to 0° C. and iodoacetonitrile (0.500 g, 0.003 mol) was added dropwise over five minutes. The reaction mixture was allowed to warm to ambient temperature and stirred for eighteen hours. The mixture was taken in ether (200 mL), washed with water (2×30 mL) and brine (1×30 mL), dried over MgSO4 and concentrated in vacuo. The resulting oily brown residue was purified by flash chromatography (8:2 ethyl acetate/hexanes) to give [1-(2-fluoro-benzenesulfonyl)-1H-indol-4-yloxy]acetonitrile as a crystalline solid (0.507 g, 77%). 1H NMR (300 MHz, CDCl3) δ: 4.87 (s, 2 H), 6.76 (d, 1 H, J=13.18), 6.77 (d, 1 H, J=1.51), 7.11 (dt, 1 H, J=8.29, J=1.13), 7.23 (t, 1 H, J=8.29), 7.29 (dt, 1 H, J=7.73, J=1.13), 758 (m, 4 H), 8.03 (m, 1 H).