Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].C([Li])CCC.[CH2:21]([O:28][C:29](=[O:42])[NH:30][CH:31]([CH:39]1[CH2:41][O:40]1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([O:28][C:29](=[O:42])[NH:30][CH:31]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:39]([OH:40])[CH2:41][CH:5]([S:6]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH2:4][CH2:3][CH:2]([CH3:15])[CH3:1])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)CCCS(=O)(=O)c1ccccc1
Reactant: O=C(NC(Cc1ccccc1)C1CO1)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CCC(CC(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.0 equivalents of (4-methyl-pentane-1-sulfonyl)-benzene (previously prepared by Gaoni, J. Org. Chem. 1982, 47, 2564) in tetrahydrofuran cooled to −78° C. is added 3.0 equivalents of n-butyl lithium and stirred for 30 min. One equivalent of (1-oxiranyl-2-phenyl-ethyl)-carbamic acid benzyl ester (previously prepared by Kaldor, et al. J. Med. Chem., 1997, p. 3979) in THF is then added dropwise and the reaction stirred for 1.5 h. The reaction is then quenched with saturated aqueous sodium bicarbonate and warmed to ambient temperature. After standard aqueous work-up and extraction, followed by concentration and silica gel chromatography the title compound is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:19](O)=[O:20])=[N:15][NH:16]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.CN.C1C=CC2N(O)N=[N:31][C:29]=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:29][NH:31][C:19]([C:14]1[C:13]2[C:17](=[CH:18][C:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[CH:11][CH:12]=2)[NH:16][N:15]=1)=[O:20]
Reactant: O=C(O)c1n[nH]c2cc(-c3ccc([N+](=O)[O-])cc3)ccc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1n[nH]c2cc(-c3ccc([N+](=O)[O-])cc3)ccc12
Temperature: 70 °C
Reaction time: 12 h
Yield: 47.3 %

Procedure:
To a stirred solution of 6-(4-nitrophenyl)-1H-indazole-3-carboxylic acid (140 mg, 0.5 mmol), methyl amine hydrochloride (45 mg, 0.6 mmol), HOBt (80 mg, 0.6 mmol), and triethylamine (0.3 Ml, 2 mmol) in N,N-dimethylformamide (5 Ml), was added EDCI (142 mg, 0.7 mmol). After the mixture was stirred at 70° C. for 12 h, the mixture was cooled to room temperature, and ethyl acetate and saturated sodium bicarbonate solution were added. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give N-methyl-6-(4-nitrophenyl)-1H-indazole-3-carboxamide (70 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([CH2:16][CH2:17][OH:18])[C:8]=23)=[C:4]([F:21])[CH:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[C:25]([NH2:30])[N:24]=1.Cl.[OH-].[Na+]>O>[NH2:30][C:25]1[N:26]=[C:27]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([CH2:16][CH2:17][OH:18])[C:8]=34)=[C:4]([F:21])[CH:3]=2)[CH:28]=[C:23]([Cl:22])[N:24]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]cc(CCO)c23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Oc3ccnc4[nH]cc(CCO)c34)c(F)c2)n1

Procedure:
56 mg (0.17 mmol) of 2-[4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]ethanol and 30 mg (0.18 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 5 ml of water. 25 μl of 37% strength hydrochloric acid are added, and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the pH is then adjusted to 10, resulting in the precipitation of crystals. The mixture is concentrated and filtered through silica gel. The product is purified by preparative HPLC.
Reaction SMILES: [Na].CN([SiH3])[Si](C)(C)C.O1C[CH2:12][CH2:11][CH2:10]1.O1CCCC1.[CH:19]1([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20]1.C(Br)C=C>O>[CH:19]1([CH:23]([CH2:12][CH:11]=[CH2:10])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20]1
Reactant: C1CCOC1
Reactant: CCOC(=O)CC1CCC1
Agent: CN([SiH3])[Si](C)(C)C
Agent: [Na]
Solvent: C=CCBr
Solvent: O
Product: C=CCC(C(=O)OCC)C1CCC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A 1.9 M tetramethyldisilazane sodium-tetrahydrofuran solution (9.44 mL, 18.0 mmol) was added dropwise over 10 minutes to a tetrahydrofuran (40 mL) solution of ethyl 2-cyclobutylacetate (2.32 g, 16.3 mmol) cooled to −78° C., and the mixture was then stirred at −78° C. for 10 minutes. Subsequently, a tetrahydrofuran (10 mL) solution of allyl bromide (7.90 g, 65.3 mmol) was added dropwise thereto over 10 minutes, and the mixture was stirred at room temperature for 17 hours. The mixture was treated with water, and volatile portions were then removed under reduced pressure. To the obtained liquid, ethyl acetate and water were added, and the obtained organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a yellow oil substance (1.80 g, 61%).
Reaction SMILES: [O:1]1[C:5]2=[N:6][C:7]3[C:12]([C:13]([NH:14][C:15]4[CH:20]=[CH:19][C:18](/[C:21](=N/O)/[CH3:22])=[CH:17][CH:16]=4)=[C:4]2[CH:3]=[CH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C[O:26]/N=C(/C1C=CC(NC2C3C(=CC=CC=3)N=C3OC=CC=23)=CC=1)\C.COC1C=C(NS(C)(=O)=O)C=CC=1NC1C2C=CC=CC=2N=C2C=CC=CC=12>>[O:1]1[C:5]2=[N:6][C:7]3[C:12]([C:13]([NH:14][C:15]4[CH:20]=[CH:19][C:18]([C:21](=[O:26])[CH3:22])=[CH:17][CH:16]=4)=[C:4]2[CH:3]=[CH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: C/C(=N\O)c1ccc(Nc2c3ccccc3nc3occc23)cc1
Reactant: CO/N=C(\C)c1ccc(Nc2c3ccccc3nc3occc23)cc1
Agent: COc1cc(NS(C)(=O)=O)ccc1Nc1c2ccccc2nc2ccccc12
Product: CC(=O)c1ccc(Nc2c3ccccc3nc3occc23)cc1

Procedure:
In addition, (E)-1-(4-(furo[2,3-b]quinolin-4-ylamino)phenyl)ethanone oxime (a hydroxyimino derivative of compound 1, referred to as compound 2 hereinafter) and (E)-1-(4-(furo[2,3-b]quinolin-4-ylamino)phenyl)ethanone O-methyloxime (a methoxyimino derivative of compound 1, referred to as compound 3 hereinafter) were also shown to have an antiproliferative potency comparable to that of amsacrine. The applicants even further found that compound 1 is able to induce mitotic arrest and apoptosis by binding to tubulin and inhibiting tubulin polymerization (Huang Y. T. et al. (2005), J. Med. Chem., 280:2771-2779).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=O)=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].O>CCO>[Br:1][C:2]1[CH:3]=[C:4]([S:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OSc1cnc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-Bromo-6-chloro-pyridine-3-sulfonyl chloride (2.5 g, 8.6 mmol), sodium sulfite (2.0 g, 16.1 mmol), and sodium bicarbonate (1.4 g, 16.9 mmol) were dissolved into water (8 mL) and EtOH (3 mL). The reaction mixture was allowed to stir at RT for 12 hours. TLC analysis showed loss of SM and formation of a very polar new spot. Reaction mixture was concentrated in vacuo resulting in a white solid and was used without further purification. ESI-MS (m/z): Calcd. for C5H3BrClNO2S: 255.8 (M+H); found: 256.0. 1H-NMR (CD3OD): δ 8.55 (m, 1H), 8.29 (m, 1H).
Reaction SMILES: [CH2:1]1[CH2:22][O:21][C:3]2([CH2:8][CH2:7][C:6]([C:9]3[CH:14]=[C:13]([F:15])[C:12]([C:16]([F:19])([F:18])[F:17])=[C:11]([F:20])[CH:10]=3)=[CH:5][CH2:4]2)[O:2]1.[H][H]>C(O)C.[Pd]>[CH2:22]1[CH2:1][O:2][C:3]2([CH2:4][CH2:5][CH:6]([C:9]3[CH:14]=[C:13]([F:15])[C:12]([C:16]([F:17])([F:18])[F:19])=[C:11]([F:20])[CH:10]=3)[CH2:7][CH2:8]2)[O:21]1
Reactant: [H][H]
Reactant: Fc1cc(C2=CCC3(CC2)OCCO3)cc(F)c1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: Fc1cc(C2CCC3(CC2)OCCO3)cc(F)c1C(F)(F)F
Yield: 90.2 %

Procedure:
1,1-Ethylenedioxy-4-(3',5'-difluoro-4'-trifluoromethylphenyl)-3-cyclohexene (17.3 g) was dissolved in ethanol (200 ml), followed by adding Pd/C (5%) (5 g), carrying out a catalytic reduction with stirring in a hydrogen gas atmosphere, filtering off the catalyst after completion of the reaction, and distilling off the organic layer under reduced pressure, to obtain 1,1-ethylenedioxy-4-(3',5'-difluoro-4'-trifluoromethylphenyl)cyclohexane (15.7 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.[NH2:11][C:12]1[N:17]=[CH:16][C:15]2[C:18]([CH3:26])([CH3:25])[C:19](=[O:24])[N:20]([CH:21]3[CH2:23][CH2:22]3)[C:14]=2[CH:13]=1>>[CH:21]1([N:20]2[C:14]3[CH:13]=[C:12]([NH:11][C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[N:3][CH:4]=4)=[O:10])[N:17]=[CH:16][C:15]=3[C:18]([CH3:25])([CH3:26])[C:19]2=[O:24])[CH2:23][CH2:22]1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Reactant: Cc1ncc(C(=O)O)cn1
Product: Cc1ncc(C(=O)Nc2cc3c(cn2)C(C)(C)C(=O)N3C2CC2)cn1

Procedure:
Prepared in analogy to example 26 from 2-methylpyrimidine-5-carboxylic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (example 79c). The title compound was obtained as light yellow crystals.
Reaction SMILES: C([N:4]1[C:28](=[O:29])[C:7]2=[N:8][N:9]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)=[CH:19][CH:18]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]2=[N:5]1)C=C.C[N+]1([O-])CCOCC1.I([O-])(=O)(=O)=O.[Na+].C(=O)(O)[O-].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O.O>[N:23]1([C:20]2[CH:21]=[CH:22][C:17]([CH2:16][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:6]4=[N:5][NH:4][C:28](=[O:29])[C:7]4=[N:8]3)=[CH:18][CH:19]=2)[CH:27]=[CH:26][CH:25]=[N:24]1
Reactant: C=CCn1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)nc-2c1=O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)nc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Prop-2-en-1-yl-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 10), 209 mg, 0.547 mmol], N-methylmorpholine oxide (192 mg, 1.64 mmol, 3.0 equiv), osmium(VIII)tetraoxide (69.5 mg, 0.273 mmol, 0.5 equiv) and sodium periodate (292 mg, 1.37 mmol, 2.5 equiv) were combined in dioxane (10 mL) and water (1 mL) and placed into an oil bath preheated to 60° C. for 18 hours. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (20 mL, aqueous saturated) and extracted with ethyl acetate (3×25 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:1]1([C:7]2([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20](=[O:22])[CH3:21])=[CH:17][CH:18]=3)[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(C2(c3ccccc3)CCCCO2)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C2(c3ccccc3)CCCCO2)cc1
Temperature: 25 °C

Procedure:
4-(2-Phenyl-tetrahydro-pyran-2-yl)-phenol (500 mg, 2 mmol) was dissolved in pyridine (10 mL). Acetic anhydride (1 mL) was added at drop wise at 0° C. The reaction temperature was allowed to raise to room temperature. After 1 h the reaction was quenched the addition of water (5 mL). Dichloromethane (20 mL) was added. The organic phase was washed with aqueous HCl (1M, 2×10 mL), brine (10 mL), dried (Na2SO4) and concentrated in vacuo. Purified on a short column (eluent: dichloromethane). Yield: 560 mg.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C@@H:8]1[C:13]([OH:15])=O)#[N:2].[NH2:19][CH:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:21]([OH:25])[C:22]([NH2:24])=[O:23].O[NH-].O=[N-]>>[NH2:24][C:22](=[O:23])[C:21](=[O:25])[CH:20]([NH:19][C:13]([C@H:8]1[CH2:9][CH2:10][C:11](=[O:12])[N:7]1[CH2:6][C:5]1[CH:16]=[CH:17][CH:18]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:15])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N#Cc1cccc(CN2C(=O)CC[C@@H]2C(=O)O)c1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: N#Cc1cccc(CN2C(=O)CC[C@@H]2C(=O)NC(Cc2ccccc2)C(=O)C(N)=O)c1

Procedure:
Coupling of (R)-1-(3-cyano-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [NH2:1][C:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O>O1CCCC1>[NH2:1][CH2:2][CH2:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CC(N)=O)c1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1cccc(CCN)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, ethyl 2-(3-aminocarbonylmethylphenoxy)-2-methylpropionate (507 mg, 1.91 mmol) was dissolved in tetrahydrofuran. Subsequently, borane-tetrahydrofuran complex in tetrahydrofuran solution [1M BH3-THF in THF (19.1 mL, 19.1 mmol)] was added thereto, and the mixture was stirred for one hour at 50° C. The reaction mixture was concentrated under reduced pressure, followed by addition of 1M hydrochloric acid at 0° C. and stirring at room temperature. The resultant mixture was made basic with sodium carbonate, followed by extraction with chloroform and drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=10/1), whereby the target compound was obtained (261.8 mg, 1.04 mmol, 54.5%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]([O:21][CH3:22])=[CH:19][C:6]2[S:7][C:8]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])=[C:9]([CH3:10])[C:5]=2[CH:4]=1.[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:10][C:9]1[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:20]([O:21][CH3:22])=[CH:19][C:6]=2[S:7][C:8]=1[C:11]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12]
Reactant: COc1cc2sc(C(=O)N3CCOCC3)c(C)c2cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc2sc(C(=O)N3CCOCC3)c(CBr)c2cc1OC

Procedure:
(5,6-Dimethoxy-3-methylbenzo[b]thiophen-2-yl)morpholin-4-yl-methanone (2.0 g) from Example 20, N-bromosuccinimide (1.18 g) and 2,2′-azobis(2-methylpropionitrile) (40 mg) in carbon tetrachloride (6 ml) was refluxed under argon for 4 hours. The mixture was cooled and filtered and the filtrate evaporated to dryness. The product was a mixture of (4-bromo-5,6-dimethoxy-3-methyl-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone and (3-bromomethyl-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone. The compounds were separated by flash chromatography using ethyl acetate/heptane (1:4) as an eluent.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:15][CH2:16][C:17](O)=[O:18])=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]2[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3]1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[C:45]1([C@H:51]([CH3:54])[CH2:52][NH2:53])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:15][CH2:16][C:17]([NH:53][CH2:52][C@H:51]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH3:54])=[O:18])=[CH:9][C:10]([C:11]([F:14])([F:12])[F:13])=[C:5]2[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3]1
Reactant: C[C@H](CN)c1ccccc1
Reactant: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(OCC(=O)O)nc21
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@H](CNC(=O)COc1cc(C(F)(F)F)c2c(-c3ccccc3)nn(C)c2n1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of (1-Methyl-3-phenyl-4-trifluoromethyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)-acetic acid (100 mg, 0.28 mmol), DIC (53 mg, 0.42 mmol) and HOBt (49 mg, 0.36 mmol) in DMF (5 ml) was stirred at rt for 10 min. (S)-(+)-2-Phenyl-propylamine (42 mg, 0.31 mmol) was added to the reaction mixture at rt and stirring was continued overnight at rt. After completion of the reaction, ice-cold water (10 mL) was added to the reaction mixture and the mixture was stirred for 20 min. The reaction mixture was extracted with diethyl ether, dried over sodium sulfate and concentrated under reduced pressure. The solid was triturated with pentane (20 ml×3) followed by hexane (15 ml) to yield the title compound as white solid. (100 mg, 75%). Mp=91-93° C. [1H-NMR (CDCl3, 300 MHz) δ 7.63-7.42 (m, 5H), 7.20-6.92 (m, 5H), 6.80 (s, 1H), 6.18-6.12 (m, 1H), 4.92 (dd, 2H), 4.1 (s, 3H), 3.81-3.68 (m, 1H), 3.40-3.33 (m, 1H), 2.98-2.90 (m, 1H), 1.41 (d, 3H); HPLC RtA=6.325 min. (98%); LCMS RtA=1.835, [M+H]+=469.1]
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][CH:11]([P:20](=[O:27])([O:24]CC)[O:21]CC)[P:12](=[O:19])([O:16]CC)[O:13]CC)[CH:6]=1)[CH2:2][CH2:3][CH3:4]>Cl>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][CH:11]([P:20](=[O:21])([OH:27])[OH:24])[P:12](=[O:13])([OH:16])[OH:19])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(NC(P(=O)(OCC)OCC)P(=O)(OCC)OCC)no1
Agent: Cl
Product: CCCCc1cc(NC(P(=O)(O)O)P(=O)(O)O)no1
Yield: 70.7 %

Procedure:
A solution of 4.8 g of tetraethyl [(5-n-butyl-3-isoxazolyl)amino]methylene-bis(phosphonate) in 50 ml of concentrated hydrochloric acid was heated under reflux for 3 hours. After the reaction mixture was concentrated, the solid obtained was washed with acetonitrile to give 2.5 g of [(5-n-butyl-3-isoxazolyl)amino]methylene-bis(phosphonic acid) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[I:13]I.ClC1C=CC=CC=1.OO>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[I:13]
Reactant: II
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: OO
Solvent: O
Solvent: Clc1ccccc1
Product: CCOC(=O)c1ccc(N)c(I)c1
Temperature: 90 °C

Procedure:
Ethyl 4-aminobenzoate (15.00 g, 91 mmol) and iodine (11.80 g, 46.5 mmol) were mixed with water (80 mL) and chlorobenzene (4.60 g, 41 mmol). The mixture was stirred while the temperature was gradually raised to 90° C. over 30 min. Hydrogen peroxide (30%, 50 mL) was added over 10 h at 90° C. After stirring at that temperature for an additional 6 h, the mixture was cooled and the solution decanted from the residual solids. The solids were dissolved in DCM and the solution washed successively with sodium thiosulfate and brine. After drying (MgSO4), the solvent was removed under reduced pressure and the resulting brown solid was triturated with hexane to remove di-iodinated by-products. The desired compound was obtained as a brown solid (22.85 g, 86% yield).
Reaction SMILES: [O:1]([CH:8]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.CO.Cl>O>[O:1]([CH:8]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)[CH2:9][CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(Oc1ccccc1)c1ccc(C(=O)OC)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCC(Oc1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
A mixture of methyl 4-(1-phenoxypropyl)benzoate (683 mg, 2.5 mmol) lithium hydroxide monohydrate (531 mg, 12.6 mmol), tetrahydrofuran (12 mL), methanol (4 mL) and water (4 mL) was stirred at 20° C. for 4 hours. The mixture was neutralized to pH to 1 with concentrated hydrochloric acid and then extracted with ethyl acetate (20 mL×3). The combined organic phase was separated, dried over sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 4-(1-phenoxypropyl)benzoic acid as a white solid (640 mg, 100%). LRMS (M+H)− m/z: calcd 256.11. found 256.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][C:18]1[C:23]([CH2:24]O)=[CH:22][CH:21]=[C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[N:19]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1CO
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3ccc(-c4cccc(C(F)(F)F)c4)nc3C)cc21

Procedure:
In analogy to the procedure described in example5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with [2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield the title compound as colorless crystals.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:19](O)[C@H:20]([C@H:29]([C@@H:38]([C@@H:47]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[OH:48])[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C@H:19]2[O:48][C@H:47]([CH2:49][O:50][CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C@@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:29]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:20]2[O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H](O)COCc2ccccc2)cc2ccccc21
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1c([C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc2ccccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
First, 5.85 g (7.33 mmol) of 1-C-[1-(phenylsulfonyl)indole-2-yl]-2,3,4,6-tetra-O-benzyl-D-mannitol [compound (V) wherein R1 to R4 are benzyl and R5 is phenylsulfonyl]was dissolved in toluene (500 ml). Then, 0.70 g (3.68 mmol) of paratoluene sulfate monohydrate was added to the mixture and stirred at about 100° C. for about 1 hour. After the reaction was terminated, a saturated solution of sodium hydrogen carbonate in water was added to the reaction mixture which was then subjected to extraction with diethylether. The ether solution was washed with saturated saline and dried on anhydrous sodium sulfate. After removal of the solvent by distillation, the residue was fractionated by column chromatography on silica gel [silica gel: Merck Kieselgel 60 (230-400 mesh ASTM); elution solvent: dichloromethane] to give 3.31 g (yield 58%) of (1R)-1,5-anhydro-1-C-[1-(phenylsulfonyl)indole-2-yl]-2,3,4,6-tetra-O-benzyl-D-mannitol [compound (VI) wherein R1 to R4 are benzyl and R5 is phenylsulfonyl].