Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23]CC2C=CC=CC=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>O1CCCC1.[Pd]>[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccccc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: Oc1ccccc1C1CCNCC1

Procedure:
A solution of 1-benzyloxycarbonyl-4-(2-benzyloxyphenyl)piperidine (1.22 g) in 20 mL of tetrahydrofuran was treated with 10% palladium on carbon catalyst (0.12 g) and hydrogenated at the atmospheric pressure for 16 hours. Upon filtration and evaporation of the filtrate the named product was obtained (0.36 g) as a solid; MS: 178; NMR: 1.8-1.9 (m, 4), 2.7-2.8 (m, 2), 3.0 (m, 1), 3.2 (d, J=12, 2), 5.4 (br, 2), 6.7 (d, J=8, 1), 6.8 (t, J=7, 1), 7.0-7.1 (m, 1), 7.1 (d, J=7, 2).
Reaction SMILES: CC(C)(C)C[O:4][C:5](=[O:34])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[C:16]1[CH:25]=[C:24]2[C:19]([C@H:20]([OH:33])[C@@H:21]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][O:23]2)=[CH:18][CH:17]=1.[OH-].[Na+].O>C(O)(C)C>[CH2:26]([C@@H:21]1[C@@H:20]([OH:33])[C:19]2[C:24](=[CH:25][C:16]([C:7]3[CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=[CH:11][C:6]=3[C:5]([OH:34])=[O:4])=[CH:17][CH:18]=2)[O:23][CH2:22]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)COC(=O)c1ccc(C(F)(F)F)cc1-c1ccc2c(c1)OC[C@H](Cc1ccccc1)[C@H]2O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)cc1-c1ccc2c(c1)OC[C@H](Cc1ccccc1)[C@H]2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
A solution of (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid 2,2-dimethyl-propyl ester (2.34 g, 4.69 mmol) in isopropyl alcohol (23 mL) was treated with 10% aqueous sodium hydroxide (2.3 mL, 6.4 mmol) and heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature, poured into water (34 mL), and extracted with hexanes (23 mL) and isopropyl ether (13 mL). The aqueous layer was separated and extracted with hexanes (23 mL) and isopropyl ether (13 mL), adjusted to pH 2 with 6N aqueous hydrochloric acid, and extracted with ethyl acetate (two times 40 mL). The combined ethyl acetate extracts were washed with brine (40 mL), dried over magnesium sulfate, filtered and concentrated to a white foam which was recrystallized from toluene/hexanes. The resulting solids were filtered and washed with hexanes, and the wet cake was stirred with hexanes (20 mL) for 1 hour. The mixture was filtered, and the resulting solids were dried under vacuum to provide 1.01 g (50% yield) of (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid as a white solid: 1H NMR (400 MHz, CDCl3) δ8.00 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.64 (s, 1H), 7.18-7.36 (m, 6H), 6.91 (dd, J=7.9, 1H), 6.86 (d, J=1.7 Hz, 1H), 4.53 (d, J=4.2 Hz, 1H), 4.24 (dd, J=11.2, 2.7 Hz, 1H), 3.97 (dd, J=11.0, 4.0 HZ, 1H), 2.76 (dd, J=13.9, 6.4 Hz, 1H), 2.53 (dd, J=13.7, 9.3 Hz, 1H), 2.24-2.26 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.Cl.[NH2:22][CH:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1>>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[CH:23]([NH:22][C:17]([C:15]1[CH:16]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:19])[CH2:24]2
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3ccccc3)nc12
Reactant: NC1CN2CCC1CC2
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1cc(Cl)cc2oc(-c3ccccc3)nc12
Yield: 24 %

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamide was prepared from 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid and 3-aminoquinuclidine dihydrochloride using the method outlined in Step C of Example 7. This compound was obtained in 24% yield as a white solid: mp 180-183° C.; 1H NMR (500 MHz, CDCl3) δ 9.45 (d, J=7.3 Hz, 1H), 8.22 (d, J=5.0 Hz, 2H), 8.18 (d, J=2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.64-7.47 (m, 3H), 4.29 (m, 1H), 3.51 (dd, J=7.2, 2.1 Hz, 1H), 3.05 (m, 2H), 2.91 (m, 2H), 2.80 (dd, J=10.2, 4.0 Hz, 1H), 2.15 (m, 1H), 2.04 (m, 1H), 1.78-1.60 (m, 3H); MS (APCI) m/z 382 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:28][N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: COC(=O)CCc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Product: COC(=O)CCc1ccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-(2-methoxycarbonylethyl)phenyl)propanamide (208 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(4-(2-methoxycarbonylethyl)phenyl)propanamide (111 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=1)[C:15]([OH:17])=[O:16].Cl>CN(C)C=O.O>[CH2:3]([O:10][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=1)[C:15]([OH:17])=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccnc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
To a suspension of sodium hydride (14.0 g) in N,N-dimethylformamide (250 mL) was added dropwise benzyl alcohol (20.6 g) under ice-cooling over 30 minutes and then added 2-chloroisonicotinic acid (25.0 g) thereto. The reaction solution was stirred at room temperature for 2 hours and then at 70° C. for 13 hours. The reaction solution was allowed to cool to room temperature, diluted with about decuple volumes of water, and then adjusted to pH 5 with 5N hydrochloric acid. The resulting crystals were collected by filtration and then washed with water and hexane to give the title compound as a colorless solid (12.6 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](/[CH:24]=[CH:25]/[CH:26]([OH:35])[CH2:27][CH:28]([OH:34])[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:10]([CH:21]([CH3:23])[CH3:22])[N:11]3[N:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=23)=[CH:4][CH:3]=1.CCCCCC>C(OCC)C.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](/[CH:24]=[CH:25]/[C:26](=[O:35])[CH2:27][CH:28]([OH:34])[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:10]([CH:21]([CH3:23])[CH3:22])[N:11]3[N:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=23)=[CH:4][CH:3]=1
Reactant: COC(=O)CC(O)CC(O)/C=C/c1c(-c2ccc(F)cc2)c2c3ccccc3cnn2c1C(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)CC(O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2c3ccccc3cnn2c1C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
A solution of methyl (E)-7-{1-(4-fluorophenyl)-3-isopropylpyrrolo[2,1-a]phthalazin-2-yl}-3,5-dihydroxyhept-6-enoate (3.16 g) in anhydrous diethyl ether (100 ml) was treated with activated manganese dioxide (12.61 g) and the mixture was stirred at room temperature under an argon atmosphere with the exclusion of light for 18 hours. The mixture was then filtered through diatomaceous earth. The filter pad was washed with diethyl ether (2×150 ml) and the combined filtrate and washings were concentrated to give an orange foam. This foam was subjected to flash chromatography on silica gel, using a mixture of diethyl ether and hexane (4:1 v/v) as eluant, to give methyl (E)-7-{1-(4-fluorophenyl)-3-isopropylpyrrolo[2,1-a]phthalazin-2-yl)-3-hydroxy-5-oxohept-6-enoate (1.61 g), in the form of an orange foam. [NMR (in CDCl3): 1.59 (6H, d, J=8 Hz), 2.55 (4 H, m), 3.45-4.15 (5 H, m), 4.40 (1H, m), 5.82 (1H, d, J=16 Hz), 7.05-7.70 (8H, m), 7.85 (1H, d, J=16 Hz), 8.30 (1H, s)].
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][CH2:15][CH2:16][N:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[N:19]=[C:18]1[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:13]>CC(O)C>[CH2:12]([O:14][CH2:15][CH2:16][N:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[N:19]=[C:18]1[CH2:26][N:27]1[CH2:28][CH2:29][N:30]([CH2:11][CH:9]([CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:10])[CH2:31][CH2:32]1)[CH3:13]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CCOCCn1c(CN2CCNCC2)nc2cccnc21
Solvent: CC(C)O
Product: CCOCCn1c(CN2CCN(CC(O)COc3ccccc3)CC2)nc2cccnc21
Reaction time: 20 h
Yield: 31 %

Procedure:
A mixture of 1.65 parts of 2-(phenoxymethyl)oxirane, 8.9 parts of 3-(2-ethoxyethyl) -2-(1-piperazinylmethyl)-3H-imidazo[4,5-b]pyridine and 40 parts of 2-propanol was stirred for 20 hours at reflux temperature. The reaction mixture was evaporated and the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.36 parts (31.0%) of 4-[[3-(2-ethoxyethyl)-3Himidazo[4,5-b]pyridin-2-yl]methyl]-α-(phenoxymethyl)-1-piperazineethanol; mp. 102.5° C. (compound 118).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.[CH3:19][O:20][CH2:21][CH2:22][OH:23]>[Na]>[NH2:1][C:2]1[N:10]=[C:9]([O:23][CH2:22][CH2:21][O:20][CH3:19])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1
Reactant: Nc1ncnc2c1ncn2Cc1ccc(F)cc1
Reactant: COCCO
Agent: [Na]
Product: COCCOc1nc(N)c2ncn(Cc3ccc(F)cc3)c2n1
Temperature: 20 °C
Yield: 95 %

Procedure:
6-Amino-9-(4-fluorobenzyl)purine (100 mg, 0.36 mmol) was dissolved in 30 ml of sodium 2-mehoxyethoxide in 2-methoxyethanol and the solution was heated at 20° C. for 3 hours. The reaction mixture was concentrated in vacuo to dryness and to the residue was added water. The mixture was extracted with chloroform and the organic layer was washed with water, dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (109 mg, yield 95%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)C>[C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:26][CH2:25][N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:9][CH:8]=2)[N:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CN1CCN(CCO)CC1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(O)cc2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCN(CCOc2ccc(-n3nc(C(C)(C)C)cc3N)cc2)CC1
Reaction time: 1.25 h
Yield: 15.1 %

Procedure:
To a solution of Intermediate 13b (1.15 g, 5.0 mmol), 2-(4-methyl-piperazin-1-yl)-ethanol (864 mg, 6.0 mmol), and triphenylphosphine (2.62 g, 10.0 mmol) in THF (10 mL), was added diisopropyl azodicarboxylate (2.0 g, 10.0 mmol) dropwise and stirred for 75 min. The mixture was diluted with diethyl ether (50 mL) and extracted with 10% aqueous citric acid soln (2×). The combined aqueous layers were basified with solid potassium carbonate until pH=9. The aqueous layer was then extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried (NaSO4) and evaporated in vacuo. Purification by FCC using 0-12% [9:1 MeOH/880 ammonia] in DCM. The resulting product was crystallised (diethyl ether) to give the title compound (270 mg, 0.756 mmol, 15%). LCMS (Method 1): Rt 2.31, 1.72 min, m/z 358/359 [MH+].
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([SH:8])=[N:4]1.[CH:9](N(C(C)C)CC)(C)C.CI>CO>[OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([S:8][CH3:9])=[N:4]1
Reactant: OC[C@@H]1CSC(S)=N1
Reactant: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CI
Product: CSC1=N[C@H](CO)CS1
Yield: 59 %

Procedure:
To a mixture solution of 4.88 g of 4(R)-hydroxymethyl-2-mercapto-1,3-thiazoline [Compound (5)] and 22.8 ml of diisopropylethylamine in 65 ml of dry methanol was added 14.00 g of methyl iodide under refluxing condition, and the reaction mixture was refluxed for 1 hour. After removal of the solvent under reduced pressure, the resulting residue was dissolved in ethyl acetate and the organic layer was washed with saturated sodium bicarbonate solution, water and saturated saline solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-acetone) to give 3.14 g (59%) of 4(R)-hydroxymethyl-2-methylthio-1,3-thiazoline [Compound (6)].
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[N:21][N:22]=3)[N:19]=2)[O:11][N:10]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][CH2:23][C:20]1[N:18]2[N:19]=[C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:8][OH:7])[CH:13]=3)[CH:15]=[CH:16][C:17]2=[N:22][N:21]=1
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(-c3cc(COC4CCCCO4)no3)nn12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1nnc2ccc(-c3cc(CO)no3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (6-(3-((tetrahydro-2H-pyran-2-yloxy)methyl)isoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (4.73 g, 11.0 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (16.9 ml, 220 mmol). The mixture was stirred at room temperature for one hour, then was concentrated, taken up in 2.0 M ammonia in methanol and purified by MPLC chromatography (eluted with 0-10% (1:10:90 NH4OH:MeOH:DCM) in DCM) to yield the product as a tan solid. MS m/z=246.9 [M+1]+. Calc'd for C10H10N6O2: 246.1.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH:10]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([CH:25]([CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)O)=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(OCCO)C.[OH-].[Na+]>O>[N:1]1([CH2:7][CH2:8][CH:9]=[CH:10][C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([CH:25]=[CH:27][CH2:28][CH2:29][N:30]5[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]5)=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(O)CCCN3CCCCC3)ccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCCO
Product: C(=Cc1ccc2c(c1)Cc1cc(C=CCCN3CCCCC3)ccc1-2)CCN1CCCCC1
Temperature: 80 °C

Procedure:
A mixture of 4.7 g (0.01 mole) of α,α'-bis(3-piperidinopropyl)-2,7-fluorenedimethanol, 25 ml of concentrated hydrochloric acid and 25 ml of ethylene glycol monoethyl ether is heated at 80°C. for 5 minutes. The solution is diluted with water, made alkaline with a 20% sodium hydroxide solution and the solution is extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue is crystallized from isopropanol resulting in the preparation of crystalline 2,7-bis(4-piperidino-1-buten-1-yl)fluorene.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)=[O:5])C.[OH-].[Li+]>CO.O1CCOCC1.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:11]=[CH:10][C:9]([C@@H:7]3[CH2:8][C@H:6]3[C:4]([OH:5])=[O:3])=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(-c2ccc(F)cc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(-c2ccc(F)cc2)nc1
Temperature: 70 °C

Procedure:
3.00 g (10.5 mmol) of trans-2-[6-(4-fluoro-phenyl)-pyridin-3-yl]-cyclopropanecarboxylic acid ethyl ester and 378 mg (15.8 mmol) of lithium hydroxide were dissolved in a mixture of 27 ml of methanol, 5 ml of dioxane and 3 ml of water, and the mixture was heated at 70° C. for 2 h. Subsequently, the mixture was evaporated to dryness, the residue was taken up in water and the pH was adjusted to 4 with acetic acid. The precipitate was isolated by filtration and purified by column chromatography (silica gel, dichloromethane/methanol, gradient from 98:2 to 95:5). Yield: 2.2 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[C:7]=1[N+:13]([O-:15])=[O:14].[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>>[NH2:12][C:8]1[C:7]([N+:13]([O-:15])=[O:14])=[C:6]([O:5][C:4]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([O:22][C:21]([F:20])([F:32])[F:33])[CH:24]=3)[CH:3]=2)[CH:11]=[CH:10][N:9]=1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Nc1cc(Oc2ccnc(N)c2[N+](=O)[O-])ccc1Cl
Product: Nc1nccc(Oc2ccc(Cl)c(NC(=O)c3cccc(OC(F)(F)F)c3)c2)c1[N+](=O)[O-]
Yield: 33 %

Procedure:
Method H was used with 4-(3-amino-4-chlorophenoxy)-3-nitropyridin-2-amine and 3-(trifluoromethoxy)benzoyl chloride to afford the title compound as a yellow solid (0.153 g, 33%). 1H NMR δ (DMSO): 6.11 (d, 1H, Hpy,5, J=5.5 Hz), 7.18 (dd, 1H, Harom,5, J=3+9 Hz), 7.23 (s, 2H, NH2), 7.53 (d, 1H, Harom,2, J=3 Hz), 7.63 (dt, 1H, Harom, J=1+8 Hz), 7.66 (d, 1H, Harom,6, J=9 Hz), 7.70 (t, 1H, Harom,5, J=8 Hz), 7.91 (s, 1H, Harom,2′), 8.02 (dt, 1H, Harom, J=1+8 Hz), 8.07 (d, 1H, Hpy,6, J=5.5 Hz), 10.63 (s, 1H, NHamide). 19F NMR δ (DMSO): −56.37 (s, 3F, CF3).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH:7]([N:16]([CH3:33])[C:17](=[O:32])[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)C.O.[OH-].[Li+].O.Cl>C1COCC1.CO.O>[CH3:33][N:16]([CH:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[CH2:6][CH2:5][C:4]([OH:34])=[O:3])[C:17](=[O:32])[C:18]1[CH:19]=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=1
Reactant: CCOC(=O)CCC(Cc1ccc(Cl)cc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1ccc(Cl)cc1

Procedure:
A solution of 25 g of 4-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(4-chloro-phenyl)-pentanoic acid ethyl ester and 18 g of lithium hydroxide monohydrate in 120 ml of THF/methanol/water 3:3:1 is stirred at room temperature for 4 hours and then 200 ml of water and 1N hydrochloric acid are added (pH value approx. 2). The mixture is extracted twice with ethyl acetate. The combined organic phases are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. The residue is recrystallised from diethyl ether/petroleum ether. In this way the title compound is obtained in the form of white crystals (m.p. 125-127°).
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[CH2:12][N:11]([CH2:22][C:23]([F:26])([F:25])[F:24])[C@@H:10]1[CH2:27][O:28]CC1C=CC=CC=1)C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>C(O)C.[Pd]>[OH:8][C@H:9]1[C@H:13]([OH:14])[CH2:12][N:11]([CH2:22][C:23]([F:26])([F:24])[F:25])[C@@H:10]1[CH2:27][OH:28]
Reactant: FC(F)(F)CN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: OC[C@@H]1[C@@H](O)[C@H](O)CN1CC(F)(F)F
Yield: 69.7 %

Procedure:
(2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethyl-1-(2,2,2-trifluoroethyl)pyrrolidine (Compound 6) (0.3 g, 0.6 mmol) was dissolved in 96% ethanol (30 ml), and 10% Pd/C (0.1g) was added under N2. The compound was reduced in a Parr apparatus (40 Psi) for 16 hours. The reaction mixture was filtered and evaporated in vacuo giving (2R,3R,4R)-3,4-dihydroxy-2-hydroxymethyl-1-(2,2,2-trifluoroethyl)pyrrolidine (0.09 g) as an brown oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16][CH:17]([OH:22])[C:18]([CH3:21])([CH3:20])[CH3:19])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16][CH:17]([OH:22])[C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(CC(O)C(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N)c(CC(O)C(C)(C)C)c1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of tert-butyl[4-methoxy-2-(2-hydroxy-3,3-dimethylbutyl)phenyl]carbamate (234 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) at room temperature, and the mixture was stirred for one hour. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (40 mL) and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (157 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16]([C:18]1[N:22]([CH3:23])[C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]([C:18]1[N:22]([CH3:23])[C:21]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: O=S(=O)(NCC1CC1)c1ccc(Br)cc1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NCC2CC2)cc1
Reaction time: 16 h
Yield: 4.8 %

Procedure:
According to general procedure B, 4-bromo-N-(cyclopropylmethyl)benzenesulfonamide (116 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)benzenesulfonamide (6 mg, 5%) was provided after purification. MS (ESI) m/z 315. HPLC purity 100.0% at 210-370 mn, 10.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.