Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:32])[C:17]2[N:22]=[C:21]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[CH:24]3)[CH:20]=[CH:19][N:18]=2)[CH2:12]1)=O)C1C=CC=CC=1.Br>C(Cl)Cl.C(O)(=O)C>[NH:11]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:32])[C:17]2[N:22]=[C:21]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[CH:24]3)[CH:20]=[CH:19][N:18]=2)[CH2:12]1
Reactant: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCN(C(=O)OCc2ccccc2)C1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a 0° C. solution of 150 mg of 2-[(1-(benzyloxycarbonyl)-pyrrolidin-3-yl)-methylamino]-4-[benzimidazol-1-yl]pyrimidine (from EXAMPLE 11, step C) in 3 mL of CH2Cl2 was added 1 mL of 30% HBr in acetic acid. The cooling bath was removed after 5 min and the mixture was stirred at room temperature for 1 h, then diluted with 20 mL of water and extracted with 2×5 mL of CH2Cl2. The pH of the aqueous phase was adjusted to 11 with 5 N NaOH, and the aqueous phase was extracted with 5×10 mL of EtOAc, with continuous monitoring of the pH. The combined EtOAc extracts were dried over MgSO4 and concentrated to yield 40 mg of the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 8.62 (s, 1H), 8.38 (br s, 1H) 8.18 (d, J=7.6 Hz, 1H), 7.85 (dd, J=1.8, 7.1 Hz, 1H), 7.33-7.42 (m, 2H), 6.79 (d, J=5.5 Hz, 1H), 3.52 (t, J=6.4 Hz, 2H), 3.03-3.16 (m, 2H), 2.71-3.00 (m, 1H), 2.79 (dd, J=5.7, 11.0 Hz, 1H), 2.46-2.37 (m, 1H), 1.96-2.20 (m, 1H), 1.52-1.60 (m, 1H).
Reaction SMILES: [C:1]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[CH2:19](I)[CH3:20]>>[C:1]([N:8]([CH2:19][CH3:20])[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCI
Reactant: CCOC(=O)C(=O)Nc1c(C)cccc1[N+](=O)[O-]
Product: CCOC(=O)C(=O)N(CC)c1c(C)cccc1[N+](=O)[O-]

Procedure:
N-ethoxalyl-N-ethyl-2-nitro-6-methylaniline (oil) was prepared from N-ethoxalyl-2-nitro-6-methylaniline and ethyl iodide.
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:8]([C:9]([O:11][CH:12](C)[CH:13]([C:18]#[N:19])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:10])=[CH:7][CH:6]=1)(=O)C.[CH2:23](N)C1C=CC=CC=1>CCOCC>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH2:12][C:13]([C:18]#[N:19])([CH3:23])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:10])=[CH:21][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CCCCC(C#N)C(C)OC(=O)c1ccc(OC(C)=O)cc1
Solvent: CCOCC
Product: CCCCC(C)(C#N)COC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.6 %

Procedure:
482 mg (1.6 mM) of 2-cyano-2-methylhexyl p-acetoxybenzoate obtained in Step 1) was dissolved in 1.5 ml of dry ether, and a solution of 188 mg (1.6 mM) of benzylamine in 1 ml of ether was added thereto, followed by 24 hours of stirring at room temperature. After the reactions and distilling-off of the solvent, the product was purified by thin layer chromatography (developer solvent: ethyl acetate/methylene chloride=1:5) to obtain 339 mg of 2-cyano-2-methylhexyl p-hydroxybenzoate (yield 73.7%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13]>N1C=CC=CC=1>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: NCCCCN
Reactant: Clc1cnccn1
Solvent: c1ccncc1
Product: NCCCCNc1cnccn1

Procedure:
(4-aminobutyl)pyrazin-2-ylamine was prepared by refluxing 2-chloropyrazine and 1,4-diaminobutane in pyridine (50 mL) for 18 hrs. The solution was then concentrated in vacuo and the residue was partitioned between ethyl acetate and 10% sodium carbonate. The phases were separated, and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The desired product was isolated by flash chromatography using 10:1:1 Ethanol/Ammonium Hydroxide/water. EI-MS m/z 167 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([Cl:17])[N:14]=[N:15][CH:16]=[C:11]2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19]Br>ClCCl>[CH2:1]([N:8]1[C:12]2=[C:13]([Cl:17])[N:14]=[N:15][CH:16]=[C:11]2[C:10]([Br:19])=[C:9]1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2cnnc(Cl)c2n1Cc1ccccc1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1c(Br)c2cnnc(Cl)c2n1Cc1ccccc1
Yield: 83 %

Procedure:
8.0 g (31 mmol) of 1-benzyl-7-chloro-2-methylpyrrolo[2,3-d]pyridazine and 1.59 ml (31 mmol) of bromine are reacted in a total of 150 ml of dichloromethane as described for Example 3a. Yield: 83%, m.p.: 138°-140° C.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[C:5]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:11][C@@H:10]1Br)(=[O:7])[CH3:6]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:5]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:11][C@H:10]1[N:3]=[C:2]=[S:1])(=[O:7])[CH3:6]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#C[S-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](N=C=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 76 %

Procedure:
Potassium thiocyanate (2.81 g, 28.7 mmol), tetrabutylammonium hydrogen sulphate (1.22 g, 3.59 mmol) and molecular sieves (6.00 g) were stirred in absolute acetonitrile (500 ml) for 30 minutes. 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide 37 (5.90 g, 14.4 mmol) was then dissolved in acetonitrile, added to the reaction flask and refluxed for 90 minutes. The solution was then allowed to cool, filtered through a celite pad and concentrated. Purification by column chromatography in hexane:ethyl acetate 2:1 (v/v) to give 52 (4.26 g, 76%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)=[N:6][CH:7]=1.[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:5]2[N:4]=[CH:3][C:2]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][OH:25])=[CH:7][N:6]=2)=[N:9]1
Reactant: Fc1ccccc1Cn1nc(-c2ncc(Br)cn2)c2cccnc21
Reactant: OCc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: OCc1ccccc1-c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1

Procedure:
200 mg (0.52 mmol) of 3-(5-bromo-2-pyrimidinyl)-1-(2-fluorobenzyl)-1H-pyrazolo-[3,4-b]pyridine (example I, step 6), 90 mg (0.62 mmol) of 2-(hydroxymethyl)-phenylboronic acid, 40 mg (0.05 mmol) of 1,1′-bis(diphenylphosphino)-ferrocenepalladium(II) chloride and 200 mg (0.62 mmol) of cesium carbonate are taken up in 2 ml of DME and stirred under reflux overnight. The solvent is removed under vacuum, and the residue is purified by preparative HPLC to result in 111 mg (52% of theory) of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.O>[CH3:14][C:11]1([CH3:13])[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[S:35]([CH3:34])(=[O:37])=[O:36])=[CH:3][CH:4]=2)=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[C:10]1=[O:15]
Reactant: CC1(C)OC(c2ccc(N)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC1(C)OC(c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
To a stirred solution of 5-(4-aminophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (60 mg, 0.13 mmol) in DCM (5 mL) were added methane sulfonyl chloride (0.012 g, 0.15 mmol) and TEA (0.04 mL, 0.27 mmol) at 0° C. under N2 atmosphere. The reaction mixture was stirred at RT for 10 min. The reaction mixture diluted with water and extracted with DCM (2×10 mL). The combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)-N-(methylsulfonyl)methane sulfonamide (25 mg, 30%), as a white color solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (d, J=8.5 Hz, 1 H), 8.10 (d, J=7.9 Hz, 1H), 7.76 (d, J=8.4 Hz, 1 H), 7.80 (d, J=8.2 Hz, 2 H), 7.74 (t, J=8.2 Hz, 1 H), 7.70 (d, J=8.5 Hz, 1 H), 7.56 (d, J=7.5 Hz, 1H), 7.28 (d, J=7.4 Hz, 2 H), 7.12 (d, J=7.5 Hz, 2 H), 7.08 (d, J=7.6 Hz, 2H), 5.42 (s, 2 H), 3.42 (s, 6 H), 1.58 (s, 6H). MS: [M+Na]: m/z=615.1, [M+H]: m/z=593.1. HPLC: 98.9% (RT-2.52 min), Column: Acquity BEH—C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH:14]([O:17][CH3:18])[O:15][CH3:16])([CH3:13])[C@H:10]([OH:19])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][C:21]3=[S:29])[C:8]=2[CH:30]=1)([O-:3])=[O:2].[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH:14]([O:15][CH3:16])[O:17][CH3:18])([CH3:13])[C@H:10]([O:19][C:31](=[O:33])[CH3:32])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][C:21]3=[S:29])[C:8]=2[CH:30]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
200 mg (0.46 mmol) of the compound obtained in Example 1 was dissolved in 2 ml of dichloromethane, to which 87 μl (0.93 mmol) of acetic anhydride, 0.13 ml (0.93 mmol) of triethylamine and 17 mg (0.14 mmol) of 4-dimethylaminopyridine were added in that order. The reaction was stirred for 2 hours at room temperature, 10 ml of saturated NaHCO3 solution was added and extraction was performed with 30 ml of dichloromethane. The extract was washed with brine and dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), to give 211 mg (yield: 97%) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])(=[O:13])[C:10]([CH3:12])=O>>[CH2:15]([O:14][C:9](=[O:13])[C@H:10]([CH3:12])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(=O)C(=O)OCC(C)C
Product: CC(C)COC(=O)[C@H](C)Nc1ccc(Cl)cc1

Procedure:
Following General Procedure AA above and using 4-chloroaniline (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.6 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant);
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12]([CH2:15][CH2:16][C:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:19])[CH3:18])(=[O:14])=[O:13].[CH2:31](I)[CH3:32]>CN(C=O)C.CCOC(C)=O>[CH2:31]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12]([CH2:15][CH2:16][C:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH3:18])[CH3:19])(=[O:13])=[O:14])[CH3:32]
Reactant: CC(C)(CCS(=O)(=O)CCOCCOCCO)NC(=O)OCc1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCCOCCOCCS(=O)(=O)CCC(C)(C)NC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 26.8 %

Procedure:
A solution of 60% sodium hydride (50 mg, 1.3 mmol) in DMF (4 ml) was cooled to 0° C. under N2 and benzyl 4-(2-(2-(2-hydroxyethoxy)ethoxy)ethylsulfonyl)-2-methylbutan-2-ylcarbamate (419.6 mg, 1.005 mmol) in DMF (1 ml) was added dropwise. Ethyl iodide (100 ul, 1.25 mmol) was added dropwise. The solution was stirred for 3 h, diluted with EtOAc (300 ml), washed with 2×100 ml sat. NaCl, dried on MgSO4, and concentrated in vacuo. The resulting residue was purified by flash chromatography (30% to 80% EtOAc in hexanes) to afford the title compound as a clear oil (119.8 mg, 0.2691 mmol, 27%). 1H NMR (CDCl3, 400 MHz) δ 1.18 (t, J=4.4 Hz, 3H), 1.32 (s, 6H), 2.17-2.21 (m, 2H), 3.12-3.17 (m, 2H), 3.48-3.58 (m, 10H), 3.87 (dd, J=5.6, 5.6 Hz, 2H), 5.03-5.06 (m, 3H), 7.3-7.4 (m, 5H). LRMS (ESI/APCI): 446 [M+H]+, 468 [M+Na]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][C@@H:9]([O:11]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][N:7]1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:5])[CH3:2].[C:32]([O-])(=[O:34])[CH3:33].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][C@H:9]([O:11][C:32](=[O:34])[CH3:33])[CH2:8][N:7]1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:23])=[O:24])=[O:5])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)[C@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1S(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H]1C[C@H](OC(C)=O)CN1S(=O)(=O)c1ccc(C)cc1
Temperature: 60 °C

Procedure:
To a stirred solution of 1-(toluene-4-sulfonyl)-4-(toluene-4-sulfonyloxy)-pyrrolidine-2-carboxylic acid ethyl ester (2) (1 g, 2.14 mmol) in dry DMF (25 mL) is added potassium acetate (0.314 g, 3.21 mmol) in one portion. The reaction mixture is then heated at 60° C. for 4 h. Water (50 mL) is added to the reaction mixture and extracted with ethyl acetate (2×75 mL), combined organic layer are washed with water (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give the crude compound. Crude compound is purified by column chromatography over silica gel (100-200 mesh) using 15% ethyl acetate-hexane as eluent to give compound (3).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)=[CH:8][C:7]=1[CH3:20].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:16]2[CH:17]=[CH:18][C:13]([O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=3)=[CH:14][CH:15]=2)=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2ccc(Br)cc2)cc1C
Product: Cc1cc(Oc2ccc(Oc3ccc(Cl)cc3Oc3ccccc3)cc2)ccc1CCC(=O)O

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(4-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-chloro-2-phenoxy-phenol as in Example 18 to afford 0.133 g (19%). 1H NMR (400 MHz, CDCl3); MS (ES−) m/z mass calculated for C28H23O5Cl 474, found 473 and 475 (M−1, and M+1, 100%).
Reaction SMILES: [OH:1][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4].C(O)[C@H]1[O:30][C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O>>[CH2:18]([OH:19])[C@H:16]1[O:17][C@@H:9]([O:8][C@@H:7]([C@H:5]([OH:6])[C@@H:3]([OH:4])[C:2]([OH:21])=[O:1])[C@H:20]([OH:30])[CH2:22][OH:23])[C@H:10]([OH:11])[C@@H:12]([OH:13])[C@@H:14]1[OH:15]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)CO

Procedure:
An aldobiose such as lactose or maltose, is electrolytically oxidised in the presence of the alkali metal carbonates/bicarbonates and alkali bromides to obtain the solution of alkali metal lactobionate, maltobionate, etc. The resulting solution is concentrated under reduced pressure to a thin syrup from which the salt is precipitated by adding 95% ethyl alcohol or isopropyl alcohol. The crude salt is dissolved in a minimum amount of hot water and then filtered through decolorizing carbon and the salt recrystallized by adding a suitable amount of the desired alcohol. The process is repeated 3-4 times to get the desired alkali salt in the pure state.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([O:20]CC)=[O:19])[C:9]2=[O:23])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([OH:20])=[O:19])[C:9]2=[O:23])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2ccccc2n(-c2cccc(C)n2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(-n2c(=O)c(C(=O)O)nc3ccccc32)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
27.2 g (88 mmol) of ethyl 1-(6-methylpyridine-2-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate was dissolved in 1,4-dioxane (50 ml) and water (50 ml), and 18.3 g (0.13 mol) of potassium carbonate was added thereto, and the solution was stirred for 1 hour at 60° C. The solvent was distilled off under reduced pressure and the aqueous layer was adjusted to pH <4. The precipitated crystals were filtered to obtain 23.3 g (yield: 94%) of 1-(6-methylpyridine-2-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid.
Reaction SMILES: [CH2:1]([O:6][CH2:7][C:8]#[CH:9])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:10]([O:12]CC)C.C([Li])CCC.C=O>CCCCCC.O>[CH2:1]([O:6][CH2:7][C:8]#[C:9][CH2:10][OH:12])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOCC
Reactant: C#CCOCCCCC
Agent: C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: CCCCCOCC#CCO
Temperature: -78 °C

Procedure:
To a 500 mL 3 neck flask equipped with magnetic stirrer, addition funnel, and nitrogen inlet was charged 10 grams (g) of 3-(pentyloxy)prop-1-yne (0.72 mmol), and 140 mL of dry ethyl ether. The reaction mixture was cooled to −78° C. with stirring followed by the dropwise addition of 37.5 mls (60 mmole) of 1.6M n-Butyl lithium solution in hexane. The temperature was adjusted to 0° C. and 5.4 g (180 mmole) of solid paraformaldehyde was added. The mixture was then stirred at ambient temperature overnight. Ether and water was added to the mixture and the ether layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum on a rotary evaporator. Isolated 9.44 g of a colorless liquid which was consistent with the desired structure upon analysis by 300 MHz 1H NMR.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=1>>[Br:15][C:16]1[N:17]=[CH:18][C:19]([C:20]([N:11]2[CH2:12][CH2:13][CH:8]([O:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:14])=[CH:6][CH:5]=3)[CH2:9][CH2:10]2)=[O:21])=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: Cc1ccc(OC2CCNCC2)cc1
Product: Cc1ccc(OC2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1
Yield: 99.9 %

Procedure:
Using 4-(p-tolyloxy)piperidine (765 mg) and 6-bromonicotinic acid (808 mg) and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (1.5 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[NH2:12][C:13]([CH3:18])([CH2:16][OH:17])[CH2:14][OH:15]>>[OH:15][CH2:14][C:13]([NH:12][S:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:10])=[O:9])([CH2:16][OH:17])[CH3:18]
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Reactant: CC(N)(CO)CO
Product: CC(CO)(CO)NS(=O)(=O)c1cncc(Br)c1
Yield: 26.1 %

Procedure:
Prepared by general procedure III from 5-bromo-pyridine-3-sulfonyl chloride (Example B.2 step 2) (500 mg, 2 mmol) and 2-amino-2-methyl-1,3-propanediol (1.03 g, 10 mmol) to give the title compound as a light brown oil (170 mg, 26%). MS (ISP) 325.1 [(M+H)+], 327.2 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:12]([C:13]3[C:14]([C:18]#[N:19])=[N:15][NH:16][CH:17]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:25][N:24]=1>CC(O)(C)C>[C:33]1([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([NH:1][C:2]3[CH:21]=[CH:20][C:5]([O:6][C:7]4[C:12]([C:13]5[C:14]([C:18]#[N:19])=[N:15][NH:16][CH:17]=5)=[CH:11][CH:10]=[CH:9][N:8]=4)=[CH:4][CH:3]=3)=[N:24][N:25]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: N#Cc1n[nH]cc1-c1cccnc1Oc1ccc(N)cc1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Solvent: CC(C)(C)O
Product: N#Cc1n[nH]cc1-c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
In a 20-mL sealed tube was dissolved 4-(2-(4-aminophenoxy)pyridin-3-yl)-1-H-pyrazole-3-carbonitrile (0.120 g, 0.433 mmol) in t-BuOH (1.0 mL). Then 1-chloro-4-phenylphthalazine (0.104 g, 0.433 mmol) was added and the mixture was stirred at 100° C. for 3 days. The reaction was cooled to RT, concentrated and purified on a Gilson reverse phase chromatography system. The title compound was extracted into CH2Cl2, washed 1× saturated NaHCO3, 1×H2O, dried over Na2SO4, filtered through fritted funnel and concentrated. The title compound was further purified by silica gel chromatography using 10-100% EtOAc/Hexanes to afford 4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1-H-pyrazole-3-carbonitrile as light yellow solid. MS m/z=482 [M+1]+. Calc'd for C29H19N7O: 481.51.
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:40])[N:9]=[C:10](SC)[C:11]([C:25]1[C:26]([F:37])=[C:27]2[C:32](=[C:33]([O:35][CH3:36])[CH:34]=1)[O:31][CH2:30][CH2:29][CH2:28]2)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.C[O:42][C:43]([C:45]1[S:46][CH:47]=[CH:48][C:49]=1[NH:50][NH2:51])=[O:44]>C(N(CC)CC)C>[F:37][C:26]1[C:25]([CH:11]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:17][CH:18]=2)[C:10]2[NH:9][C:8](=[O:40])[N:50]([C:49]3[CH:48]=[CH:47][S:46][C:45]=3[C:43]([OH:44])=[O:42])[N:51]=2)=[CH:34][C:33]([O:35][CH3:36])=[C:32]2[C:27]=1[CH2:28][CH2:29][CH2:30][O:31]2
Reactant: COC(=O)c1sccc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)CCCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCC2
Temperature: 85 °C
Reaction time: 12 h

Procedure:
To 1 ml of a DMF solution containing 100 mg of [2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (33d)), 35 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 0.028 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for 12 hours under a nitrogen atmosphere and then concentrated. The residue was dissolved in 1.5 ml of methanol, 1.5 ml of THF, and 0.1 ml of acetic acid, and 100 mg of sodium cyanotrihydroborate was further added thereto. The mixture was stirred at room temperature for 3 hours, and 1 ml of a 5 N sodium hydroxide aqueous solution was added thereto. The mixture was stirred at room temperature overnight. Acetic acid (0.3 ml) was added to the reaction mixture, and the resulting mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product of 3-(3-{(5-fluoro-8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic acid.