Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][CH3:26])=[CH:20][CH:19]=1)[C:3]([NH:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[C:8]([F:17])[CH:7]=1)=[O:4].[F:27][B:28]([F:56])[N:29]1[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[C:30]1/[CH:36]=[C:37]1\[N:38]=[C:39]([CH2:42][CH2:43][CH2:44][CH2:45][C:46](ON2C(=O)CCC2=O)=[O:47])[CH:40]=[CH:41]\1.O.O.C(#N)C>CN(C=O)C>[F:56][B:28]([F:27])[N:29]1[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[C:30]1/[CH:36]=[C:37]1\[N:38]=[C:39]([CH2:42][CH2:43][CH2:44][CH2:45][C:46]([NH:1][CH:2]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][O:25][CH3:26])=[CH:22][CH:23]=2)[C:3]([NH:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([Si:13]([CH3:14])([CH3:15])[CH3:16])=[C:8]([F:17])[CH:7]=2)=[O:4])=[O:47])[CH:40]=[CH:41]\1
Reactant: Cc1cc(C)n(B(F)F)c1/C=C1/C=CC(CCCCC(=O)ON2C(=O)CCC2=O)=N1
Reactant: COCc1ccc(C(N)C(=O)Nc2cc(F)c([Si](C)(C)C)c(F)c2)cc1
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc(C(NC(=O)CCCCC2=N/C(=C\c3c(C)cc(C)n3B(F)F)C=C2)C(=O)Nc2cc(F)c([Si](C)(C)C)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.8 %

Procedure:
To a solution of the crude 2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide (9.07 mg, 0.02 mmol) in DMF (0.5 mL) was added 1-((5-((2Z)-2-((1-(difluoroboryl)-3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2H-pyrrol-5-yl)pentanoyl)oxy)pyrrolidine-2,5-dione (BODIPY (registered trademark) FL-C5 succinimidyl ester) (5.0 mg, 0.01 mmol) at room temperature, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; ethyl acetate/hexane), and then preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) to give 5-((2Z)-2-((1-(difluoroboryl)-3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2H-pyrrol-5-yl)-N-(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)pentanamide (3.8 mg, 5.58 μmol, 46.6%) as an orange solid, which is a fluorescent-labeled synthetic ligand.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2]2.[BrH:13].C([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C1(C)C=CC=CC=1.O>[Br:13][CH:6]1[CH2:5][CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH:1]1[OH:7]
Reactant: CCOC(=O)C1CCC2OC2C1
Reactant: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC(Br)C(O)C1
Reaction time: 0.42 h

Procedure:
To a solution of ethyl 7-oxabicyclo[4.1.0]heptane-3-carboxylate (17.8 g) in CH2Cl2 (350 mL) was added 40% HBr solution (120 mL). The biphasic mixture was stirred vigorously for 25 min, then was neutralized with aqueous NaHCO3 solution. The organic layer was collected and dried over MgSO4, then was concentrated in vacuo. The residue was diluted with toluene (120 mL), and para-toluene sulfonic acid (120 mg, 0.6 mmol) was added. The mixture was heated at 128° C. with azeotropic removal of water over 3.5 hours, then was concentrated in vacuo to afford 21 g of a brown residue, which was used in the next reaction without purification.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13](OCC)=O)=[O:9])=[CH:6][C:5]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[N:4][NH:3]1.O=[C:25]1[C:30]([C:31]([OH:33])=O)=CC(C2C=CN=CC=2)=NN1.ON1C2C=CC=C[C:44]=2N=N1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[OH:33][C:31]1[CH:44]=[CH:13][C:12]([CH2:11][NH:10][C:8]([C:7]2[C:2](=[O:1])[NH:3][N:4]=[C:5]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:6]=2)=[O:9])=[CH:25][CH:30]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: CCOC(=O)CCNC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(O)cc1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 13 for the preparation of ethyl 3-[(3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carbonyl)amino]propionate, but starting with 0.6 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 60 cm3 of N,N-dimethylformamide, 0.466 g of 1-hydroxybenzotriazole, 0.91 g of (trimethylsilyl)-2-ethoxymethoxy-4-benzylamine, 0.6 cm3 of N,N-diisopropylethylamine and 1.31 g of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, and after purification by high performance liquid chromatography on a 100×30 mm HyPURITY® 5 μm column, eluting with a mixture increasing from 25% to 95% of acetonitrile/water (containing 0.05% trifluoroacetic acid), 0.16 g of N-(4-hydroxybenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a cream-colored solid melting at a temperature above 260° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:7])#[N:2].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([O:15][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: CC(C)c1ccc(C(=O)Nc2cc(O)ccc2NC(=O)c2cccc(C#N)c2)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(NC(=O)c2cccc(C#N)c2)c(NC(=O)c2ccc(C(C)C)cc2)c1

Procedure:
Using a procedure similar to Example 2A except starting with N1-(3-cyanobenzoyl)-N2-(4-isopropylbenzoyl)-4-hydroxy-1,2-benzenediamine and ethyl bromoacetate, the title compound was obtained as a solid (78%); IR(CHCl3): 2966, 1757, 1655, 1610, 1514 cm−1; NMR(300 MHz, CDCl3): δ1.31 (m, 9H), 3.00 (m, 1H), 4.24 (t, 2H, J=6.9 Hz), 4.35 (s, 2H), 6.59 (d, 1H, J=9.0 Hz), 6.95 (s, 1H), 7.35 (m, 3H), 7.64 (m, 1H), 7.82 (d, 1H, J=7.5 Hz), 7.92 (d, 2H, J=8.1 Hz), 8.23 (d, 1H, J=7.5 Hz), 8.32 (s, 1H), 9.06 (br s, 1H), 9.61 (br s, 1H); MS(FD): 485.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10](C(OCC3C=CC=CC=3)=O)[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>>[NH:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:21](=[O:24])[CH2:22][CH3:23])[C:7]=2[CH:8]=[CH:9]1
Reactant: Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1nccc2[nH]ccc12

Procedure:
N-(1H-pyrrolo[3,2-c]pyridin-4-yl)propanamide (Intermediate 26) was prepared from benzyl 4-amino-1H-pyrrolo[3,2-c]pyridine-1-carboxylate in an analogous manner using propanoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].N1C=CC=CC=1.[NH2:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][C:28](=[O:33])[N:29]2[CH3:32])=[CH:24][CH:23]=1>O>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][C:28](=[O:33])[N:29]2[CH3:32])=[CH:24][CH:23]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: CN1C(=O)CCc2ccc(N)cc21
Solvent: c1ccncc1
Solvent: O
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3F)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-Fluoro-4-(trifluoromethyl)benzoyl chloride was added to a pyridine solution of 7-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one, followed by stirring at room temperature for 12 hours. Water was added to the reaction liquid, followed by stirring for 30 minutes and then the precipitated crystals were collected by filtration to obtain 2-fluoro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzamide.
Reaction SMILES: Cl.O[CH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[N-]C(=O)C(C)(C)C.[NH2:22][C:23]([NH2:25])=[S:24]>O1CCOCC1.C(O)(C)C>[NH2:22][C:23]1[S:24][CH2:3][C:4]2[CH:9]=[C:8]([O:10][C:11]([F:12])([F:14])[F:13])[CH:7]=[CH:6][C:5]=2[N:25]=1
Reactant: CC(C)(C)C(=O)[N-]c1ccc(OC(F)(F)F)cc1CO
Reactant: NC(N)=S
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: NC1=Nc2ccc(OC(F)(F)F)cc2CS1
Temperature: 80 °C
Yield: 84 %

Procedure:
Concentrated HCl (4 ml) is added slowly to a solution of N-[2-hydroxymethyl-4-(trifluoromethoxy)phenyl]-pivaloylamide (0.35 g, 1.2 mmol) in dioxane (3 ml) and the resulting reaction mixture heated at 80° C. for 4 hours, then diluted with isopropanol (20 ml), and thiourea (0.14 g, 1.8 mmol) added and the mixture refluxed for 20 hours. The solvent is then evaporated under vacuum and the residue diluted with H2O, basified with 2 N NaOH, and extracted with CH2Cl2. The combined organic extracts are dried over Na2SO4 and concentrated under vacuum. The residue is purified by chromatography through silica, eluting with AcOEt/petroleum ether (1:1). The product is obtained as a yellow solid, with a yield of 84%. Recrystallisation from EtOH gives a solid with m.p. 115-118° C. 1H-NMR (CDCl3): 3.87 (s, 2H), 5.16 (br s, 2H), 6.97-7.11 (m, 3H). MS (ESI): m/z 249 (M+H+).
Reaction SMILES: [B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:18].[CH3:19][O:20][C:21]1[CH:33]=[CH:32][C:24]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:23][CH:22]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:18][C:33]1[CH:32]=[C:24]([CH:23]=[CH:22][C:21]=1[O:20][CH3:19])[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(Cc2cccnc2)cc1
Reactant: [IH2+]
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Cc2cccnc2)cc1I
Reaction time: 2 h

Procedure:
Bis(pyridine)iodonium tetrafluoroborate (1.35 g, 3.64 mmol) was added to a solution of 3-(4-methoxybenzyl)pyridine (720 mg, 3.64 mmol) in 9:1 TFA:DCM (20 mL) and the mixture was stirred for 1 h at 0° C. The ice bath was removed and the reaction was stirred for 2 h. EtOAc was added and the mixture was washed with water twice, satd. sodium thiosulfate twice, dried over MgSO4, concentrated in vacuo, and purified by column chromatography to give 3-(3-iodo-4-methoxybenzyl)pyridine as a yellow oil. MS (ESI) m/z: Calculated: 325.0; Observed: 326.3 (M++1).
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][CH:9]1[CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])C1C=CC=CC=1.C(O)(=O)C.[H][H]>[Pd].O1CCCC1>[C:17]([O:16][C:14]([NH:13][CH2:12][CH:9]1[CH2:10][CH2:11][NH:8]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCC1CCN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CCN1
Yield: 92.4 %

Procedure:
A suspension of 18.8 g (68.0 mmol) of 1-benzyl-2-[(t-butoxycarbonylamino)methyl]azetidine, 8.2 g (137 mmol) of acetic acid, 1.0 g of 20% palladium on carbon and 200 ml of tetrahydrofuran was shaken in a hydrogen atmosphere at pressures of 48.3-51.7 psi and temperatures of 21.5°-27° for 16 hours. The catalyst was removed by filtration and the solvent was removed in vacuo to give 11.7 g (92%) of the title compound as a colorless viscous oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:5]([F:34])=[CH:4][N:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:36]/[OH:37])/[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:5]([F:34])=[CH:4][N:3]=1
Reactant: Cc1ccccc1[C@H](CC(=O)c1cc(Cl)ncc1F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(=N\O)c1cc(Cl)ncc1F)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 132, step 6, from 4′-[(R)-3-(2-chloro-5-fluoro-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as an off-white foam, MS (ESI−): m/z=487.2 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[C:9]([OH:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](=[O:16])([O-])[O-].[K+].[K+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CN(C)C=O>[Cl:1][C:2]1[C:10]([O:11][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[C:9]([O:12][CH2:4][C:3]2[CH:7]=[CH:8][C:9]([O:16][CH3:13])=[CH:10][CH:2]=2)[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)=[O:5]
Reactant: O=C(O)c1ccc(O)c(O)c1Cl
Reactant: COc1ccc(CBr)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c2Cl)cc1

Procedure:
2-Chloro-3,4-dihydroxybenzoic acid is p-methoxybenzylated with potassium carbonate and p-methoxybenzyl bromide in dimethylformamide to give p-methoxybenzyl 2-chloro-3,4-bis(p-methoxybenzyloxy)benzoate. This is hydrolyzed with sodium hydroxide to give 2-chloro-3,4-bis(p-methoxybenzyloxy)benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([OH:28])=O)[CH:7]=1.Cl.[NH2:42][C@@H:43]([C:45]([NH2:47])=[O:46])[CH3:44]>>[NH2:47][C:45](=[O:46])[C@H:43]([NH:42][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([N:17]2[C:18]3[C:14](=[C:13]([NH:12][CH2:11][C:10]([OH:36])([C:32]([F:34])([F:33])[F:35])[CH2:9][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:39][CH3:40])([CH3:38])[CH3:37])[CH:21]=[C:20]([CH3:22])[CH:19]=3)[CH:15]=[N:16]2)[CH:24]=1)[CH3:44]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Reactant: C[C@@H](N)C(N)=O
Agent: Cl
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N[C@H](C)C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and D-alaninamide hydrochloride.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[Br:10]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:10][C:9]1[C:5]2[CH:4]=[N:3][CH:2]=[N:1][C:6]=2[NH:7][CH:8]=1
Reactant: BrBr
Reactant: c1ncc2cc[nH]c2n1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c[nH]c2ncncc12
Reaction time: 1.5 h

Procedure:
5-Bromo-7H-pyrrolo[2,3-d]pyrimidine (7) is prepared by dissolving 7H-pyrrolo[2,3-d]pyrimidine (6) in chloroform and slowly adding Br2 in carbon tetrachloride at 0° C. After stirring for 1-2 hours, the reaction may be quenched in aqueous hydrochloric acid. Isolation by conventional means (e.g. extraction and silica gel chromatography) provides compound 7.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:8]=2[CH:7]=[C:6]([Cl:21])[C:5]=1[OH:22])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:31])C=1.O.[OH-].[Na+]>C(Cl)Cl>[Cl:21][C:6]1[C:5]2[O:22][CH:2]([CH2:3][OH:31])[CH2:1][C:4]=2[C:12]2[O:11][N:10]=[C:9]([C:13]3[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[F:19])[C:8]=2[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(O)c(Cl)cc2c(-c3c(F)cccc3F)noc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCC1Cc2c(c(Cl)cc3c(-c4c(F)cccc4F)noc23)O1
Temperature: 0 °C
Yield: 86 %

Procedure:
To the ice-cooled solution of 7-allyl-5-chloro-3-(2,6-difluorophenyl)-6-hydroxy-1,2-benzisoxazole (3.1 g) in methylene chloride (80 ml), 4.6 g of m-chloroperbenzoic acid was added in small portions under agitation, and the mixture was subsequently refluxed for 5 hours. After cooling the mixture, water and an aqueous solution of 2N sodium hydroxide were added and the mixture was subjected to extraction with methylene chloride. The methylene chloride layer was washed with water and dried. By distilling off the solvent, 2.8 g of 5-chloro-3-(2,6-difluorophenyl)-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-methanol was obtained. m.p. 166°-169° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 337.
Reaction SMILES: O.FC1C(F)=CC=CC=1C1C=C2C(=CC=1)NN=C2C(NCC1CCN(CC2OC=C(C(O)=O)N=2)CC1)=[O:20].Br[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][N:43]=[C:42]2[C:48]([NH:50][CH2:51][CH:52]1[CH2:57][CH2:56][N:55]([CH2:58][C:59]2[O:63][C:62]([C:64]([O:66]CC)=[O:65])=[CH:61][CH:60]=2)[CH2:54][CH2:53]1)=[O:49].[CH3:69][O:70][C:71]1[C:76](B(O)O)=[CH:75][CH:74]=[CH:73][N:72]=1>>[OH2:20].[CH3:69][O:70][C:71]1[C:76]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[NH:44][N:43]=[C:42]3[C:48]([NH:50][CH2:51][CH:52]2[CH2:57][CH2:56][N:55]([CH2:58][C:59]3[O:63][C:62]([C:64]([OH:66])=[O:65])=[CH:61][CH:60]=3)[CH2:54][CH2:53]2)=[O:49])=[CH:75][CH:74]=[CH:73][N:72]=1
Reactant: CCOC(=O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(Br)cc34)CC2)o1
Reactant: O=C(O)c1coc(CN2CCC(CNC(=O)c3n[nH]c4ccc(-c5cccc(F)c5F)cc34)CC2)n1
Reactant: COc1ncccc1B(O)O
Solvent: O
Product: COc1ncccc1-c1ccc2[nH]nc(C(=O)NCC3CCN(Cc4ccc(C(=O)O)o4)CC3)c2c1
Reaction time: 0.25 h

Procedure:
5-({4-[({[5-(2-Methoxypyridin-3-yl)-1H-indazol-3-yl]carbonyl}amino)methyl]piperidin-1-yl}methyl)furan-2-carboxylic acid hydrate 16 was prepared, according to the procedure described for compound 12, from compound 15 and (2-methoxypyridin-3-yl)boronic acid and using the following preparative HPLC parameters for the purification: channel A=CH3CN+0.1% formic acid; channel B=H2O+0.1% formic acid: flow=40 ml/min; gradient=10%-45% of eluent A in 15 minutes. Yield: 14 mg, 5%.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[CH2:7]([N:14]1[CH:19]=[CH:18][C:17]2[N:20]=[C:21]([S:27][CH3:28])[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:16]=2[C:15]1=[O:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(=O)(O)[O-:31].[Na+].[OH2:35]>C(O)(=O)C>[CH2:7]([N:14]1[CH:19]=[CH:18][C:17]2[N:20]=[C:21]([S:27]([CH3:28])(=[O:31])=[O:35])[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:16]=2[C:15]1=[O:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S([O-])O
Reactant: O
Reactant: CC#CCn1c(SC)nc2ccn(Cc3ccccc3)c(=O)c21
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC#CCn1c(S(C)(=O)=O)nc2ccn(Cc3ccccc3)c(=O)c21

Procedure:
A solution of 316 mg (2.0 mmol) of potassium permanganate in 10 ml of water was slowly added dropwise with stirring to a solution of 400 mg (1.24 mmol) of 5-benzyl-3-(but-2-ynyl)-2-methylsulphanyl-3,5-dihydro-imidazo[4,5-c]pyridin-4-one in 10 ml of concentrated acetic acid. After three hours at ambient temperature 400 mg of sodium bisulphite (Na2S2O5) were added and the mixture was diluted with approx. 30 ml of water. It was extracted five times with 30 ml of dichloromethane, the extracts were dried over sodium sulphate and evaporated down. The product thus obtained was further reacted without purification.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:12]=[C:11](C(O)=O)[C:10]2[C:5](=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.CC[O:24][CH2:25][CH3:26]>>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:12]=[C:11]([C:25]([C:26]2[CH:10]=[CH:11][CH:12]=[CH:3][N:4]=2)=[O:24])[C:10]2[C:5](=[C:6]([C:16]([F:17])([F:18])[F:19])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Reactant: CCOCC
Product: O=C(c1ccccn1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12

Procedure:
A process for the preparation of erythro-α-piperid-2-yl-2,8-bis-(trifluoromethyl)-quinolin-4-yl-methanol which comprises the steps of reacting 2,8-bis-(trifluoromethyl)-quinoline-4-carboxylic acid or a salt thereof with a pyrid-2-yl-magnesium halide in a cyclic saturated ether or in an aliphatic dialkyl ether or an alkoxyalkyl ether in a molar ratio of from 1:2 to 1:8 at from 0° to 80° C. to give pyrid-2-yl 2,8-bis-(trifluoromethyl)-quinolin-4-yl ketone and the latter is hydrogenated in a conventional manner to give erythro-α-piperid-2-yl-2,8-bis-(trifluoromethyl)-quinolin-4-yl-methanol.
Reaction SMILES: C([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][C:5]([CH3:15])([CH3:14])[N:4]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=O.C1(P(=[CH:42][CH:43]=[O:44])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:45](Cl)Cl>>[CH3:14][C:5]1([CH3:15])[N:4]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C@H:3](/[CH:45]=[CH:42]/[CH:43]=[O:44])[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6]1
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)[C@@H](c2ccccc2)OC1(C)C
Reactant: ClCCl
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)OC(=O)N1[C@H](/C=C/C=O)[C@@H](c2ccccc2)OC1(C)C
Temperature: 25 °C
Reaction time: 40 h
Yield: 72 %

Procedure:
To a solution of tert-butyl (4S,5R)-4-formyl-2,2-dimethyl-5-phenyl-1,3-oxazolidine-3-carboxylate (20.9, 89.1 mmol) in CH2Cl2 (150 mL) was added (triphenylphosphoranylidene) acetaldehyde (27.1 g, 89.1 mmol) and the resulting mixture was stirred at ambient temperature for 40 h. After removal of ⅓ of the solvent, hexanes was generously added and the resulting solid was filtered off. Flash chromatography on a Biotage Horizon® system (silica gel, 0 to 20% ethyl acetate in hexanes gradient then 20% ethyl acetate in hexanes) gave 16.3 g (72%) of the title compound as a yellow oil. LC/MS 354.3 (M+23).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.[CH3:18][C:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][C@H:32]2[C:40](Cl)=[O:41])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>ClCCl>[CH3:21][C:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][C@H:32]2[C:40]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)=[O:41])(=[O:30])=[O:29])=[CH:26][CH:27]=1)([CH3:18])[CH3:20]
Reactant: NCc1cccc(O)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2c3ccccc3C[C@H]2C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(S(=O)(=O)N2c3ccccc3C[C@H]2C(=O)NCc2cccc(O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
54 mg (0.53 mmol) of triethylamine are added to a suspension of 42.26 mg (0.265 mmol) of 3-(aminomethyl)phenol hydrochloride in 8 ml of dichloromethane at ambient temperature, then a solution of 100 mg (0.265 mmol) of 1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-(2S)-1H-indole-2-carbonyl chloride in 2 ml of dichloromethane is added over 10 minutes. This is left to agitate at ambient temperature for 1 hour. The reaction medium is washed with water, dried on magnesium sulfate, the solvents are evaporated and the evaporation residue is purified by silica column chromatography eluting with the help of a toluene/ethyl acetate mixture (8/2; v/v). The expected product is obtained in the form of a white solid with a yield of 51%.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[C:18](Br)=[C:17]([N+:20]([O-:22])=[O:21])[C:16]([Br:23])=[N:15]2)[N:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C(O)CC>[CH2:24]([NH:31][C:18]1[N:14]([CH2:13][CH2:12][CH2:11][N:4]2[C:5]([NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([Br:1])=[N:3]2)[N:15]=[C:16]([Br:23])[C:17]=1[N+:20]([O-:22])=[O:21])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1c(Br)nn(CCCn2nc(Br)c([N+](=O)[O-])c2Br)c1Br
Solvent: CCCO
Solvent: O
Product: O=[N+]([O-])c1c(Br)nn(CCCn2nc(Br)c([N+](=O)[O-])c2NCc2ccccc2)c1NCc1ccccc1

Procedure:
11.6 g of 1,3-bis-(3,5-dibromo-4-nitropyrazol-1-yl)propane from step 5.1 are heated together with 6.5 g of benzylamine in 180 ml of n-propanol for 1 hour at 100° C. Subsequently the reaction mixture is cooled and poured into 1000 ml water. The precipitate is filtered with suction, washed with water and dried in vacuum at 60° C.