Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.[Br:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[N:12]([CH2:32][CH3:33])[C:13]1[N:18]=[C:17]([C:19]([N:21]2[CH2:26][CH2:25][C:24]3([O:30][CH2:29][CH2:28][O:27]3)[CH2:23][CH2:22]2)=O)[CH:16]=[C:15]([CH3:31])[N:14]=1.C(O)(=O)C.C(OCC)(=O)C>C1COCC1>[Br:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[CH:6]=[CH:5][C:4]=1[N:12]([CH2:32][CH3:33])[C:13]1[N:18]=[C:17]([CH2:19][N:21]2[CH2:22][CH2:23][C:24]3([O:30][CH2:29][CH2:28][O:27]3)[CH2:25][CH2:26]2)[CH:16]=[C:15]([CH3:31])[N:14]=1
Reactant: CCN(c1nc(C)cc(C(=O)N2CCC3(CC2)OCCO3)n1)c1ccc(C(C)C)cc1Br
Agent: B
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(c1nc(C)cc(CN2CCC3(CC2)OCCO3)n1)c1ccc(C(C)C)cc1Br
Temperature: 25 °C
Yield: 53.2 %

Procedure:
A solution of borane in tetrahydrofuran (1M, 29 mL, 29 mmol) was added dropwise to a solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4,4-ethylenedioxy-piperidino)carbonyl-6-methylpyrimidinamine (1.67 g, 3.3 mmol) in anhydrous THF (7 mL) with stirring under a nitrogen atmosphere. The reaction mixture was heated to reflux temperature and stirred for 20 h, then cooled to ambient temperature. A solution of glacial acetic acid was added dropwise; then the reaction mixture was heated to reflux temperature and stirred for 4 h, then cooled to ambient temperature. The reaction mixture was concentrated in vacuo; the residue was treated with excess 1N NaOH solution, and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give an oil. Column chromatography (ethyl acetate) afforded N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4,4-ethylenedioxy-piperidino)methyl-6-methylpyrimidinamine as a pale brown oil (860 mg); CI-MS; 489, 491 (M+H).
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:17][CH:18]4[CH2:27][CH2:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]4=[O:28])[CH2:13][CH2:12]3)[C:10](=[O:29])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO.O>[C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]4[CH2:27][CH2:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C@H:19]4[OH:28])[CH2:13][CH2:12]3)[C:10](=[O:29])[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2CCC1CN1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1NCN(c2ccccc2)C12CCN(C[C@@H]1CCc3ccccc3[C@H]1O)CC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1-Phenyl-8-[(1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl)methyl]-1,3,8-triazaspiro[4.5]decan-4-one (5.0 g) is suspended in methanol (100 ml) and treated over a 20 minute period with excess sodium borohydride dissolved in water (25 ml). The resulting mixture is stirred at room temperature for 15 hours. The reaction is diluted with water (200 ml), stirred for 30 minutes, and filtered to give the crude product. Two recrystallizations of this material from absolute ethanol yield 3.8 g of isomerically pure title compound, melting point 240°-242° C.
Reaction SMILES: [CH:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[C@@H:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:30]([F:33])([F:32])[F:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:34][C@H:35]([C:43]([OH:45])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:42])[NH2:41].C([O-])(=O)C>CC(O)C>[NH2:34][C@H:35]([C:43]([OH:45])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:41])[NH2:42].[CH:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[C@@H:21]([CH2:24][C:25]([O-:27])=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:30]([F:33])([F:31])[F:32])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C[C@H]1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Agent: CC(=O)[O-]
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: CC(C)O
Product: O=C([O-])C[C@H]1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
To the crude (21.837 g) (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (41.41% w/w; 9.043 g, 19.77 mmol) containing the (S)-isomer as the ester impurity in a 200 mL round bottom flask was added IPA (150.72 mL). The mixture was heated at 60° C. under N2 till the oily residue dissolved completely. The resultant orange solution was heated at about 60° C. for 5 min. Seeds of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (362 mg) were added. The seeds were suspended in the orange solution. A 2.27 M aqueous solution of L-arginine (8.709 mL, 3.44 g, 19.77 mmol) pre-warmed to about 60° C. was added into the mixture dropwise over 30 min. A light yellow precipitate formed gradually during the addition. The suspension was stirred for about an additional 30 min. The temperature of the suspension was allowed to drop at about 0.4° C. per minute to room temperature. The mixture was agitated occasionally at room temperature overnight. The suspension was filtered and the cake was washed with IPA (3×6 mL) and EtOAc (3×15 mL). The filter cake was dried at room temperature under vacuum overnight to give L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate as a white solid (11.631 g, 44.7%): HPLC 99.38 Area %, 99.6% ee. TGA, PXRD, PLM, SEM and DSC indicated the solid as a non-solvated, crystalline compound with an average aggregates size of 18.05 microns and a melting point of 202.69° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([B:22]([OH:24])[OH:23])[CH:16]=[C:17]([C:19]([OH:21])=O)[CH:18]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>CCOC(C)=O>[CH:25]([NH:28][C:19]([C:17]1[CH:18]=[C:13]([NH:12][C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:11])[CH:14]=[C:15]([B:22]([OH:24])[OH:23])[CH:16]=1)=[O:21])([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: Nc1cc(B(O)O)cc(C(=O)O)c1
Reactant: COc1ccc(N=C=O)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)Nc2cc(B(O)O)cc(C(=O)NC(C)C)c2)cc1
Yield: 77 %

Procedure:
The general procedure for the formation of ureas using 4-methoxyphenyl isocyanate (vide supra) was carried out on resin 33 followed directly by the general procedure for the formation of amides using iso-propyl amine, PyBoP and DIPEA (vide supra) to yield a yellow solid (77% yield by mass; 65% yield by 1H NMR with EtOAc int. std.): 1H NMR (300 MHz, 5% D2O in CD3OD, the sample was made up >16 h prior to running in order to obtain full exchange of the secondary amide proton with deuterated solvents) δ 7.89 (br s, 1H), 7.80 (br s, 2H), 7.31 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H) 4.17 (h, J=7 Hz, 1H), 3.76 (s, 3H), 1.24 (d, J=7 Hz, 6H); 13C NMR (75 MHz, 5% D2O in CD3OD) δ 170.1, 157.3, 156.0, 140.0, 136.2, 133.0, 128.9, 128.0, 123.0, 121.2, 115.2, 56.1, 43.2, 22.6; IR (microscope) 3399, 3310, 2970, 1664, 1626, 1599, 1547, 1514 cm−1; HRMS (ES, m/z) calcd for C18H22BN3O5Na (M+Na)+ 394.1550. found 394.1549.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1nc2cccc(Br)n2n1
Agent: Cl
Product: O=C(Nc1nc2cccc(Br)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A3), 5.0 g; 23.5 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (8.36 g; 47.0 mmol; 2.0 eq.) as a grey powder (5.86 g, 78%). HPLC, Rt: 1.24 min. (purity 97.4%). LC/MS, M+(ESI): 319.0, M−(ESI): 318.3.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5].[C:29](=[O:32])([O-])[O-:30].[Cs+].[Cs+].Br.Br[CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>CS(C)=O>[F:21][C:20]([F:23])([F:22])[C:29]([OH:30])=[O:32].[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:37][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])[N:8]=1)=[O:5]
Reactant: O=C(Nc1ccn(Cc2ccc(O)cc2C(F)(F)F)n1)c1c(F)cccc1F
Reactant: BrCc1ccncc1
Reactant: O=C([O-])[O-]
Agent: Br
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(Nc1ccn(Cc2ccc(OCc3ccncc3)cc2C(F)(F)F)n1)c1c(F)cccc1F
Product: O=C(O)C(F)(F)F
Reaction time: 7 h

Procedure:
To a solution of 2,6-difluoro-N-(1-{[4-hydroxy-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Example 36)(100 mg, 0.252 mmol) in DMSO (1 ml) was added cesium carbonate (165 mg, 0.506 mmol) and then 4-(bromomethyl)pyridine hydrobromide (90 mg, 0.356 mmol, Aldrich) under nitrogen at ambient temperature. The resulting dark green suspension was then stirred for 7 h. A further amount of cesium carbonate (161 mg, 0.494 mmol) and then 4-(bromomethyl)pyridine hydrobromide (90 mg, 0.356 mmol, Aldrich) was added to the reaction mixture and stirred overnight. The mixture was filtered using a hydrophobic frit and the filtrate diluted with methanol (1 ml). The filtrate was purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a TFA modifier (Method C). The solvent was evaporated in vacuo to give the title compound as a brown gum (44 mg);
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41]>O1CCCC1>[CH3:38][N:39]([CH3:43])[C:40]([N:19]1[CH2:20][CH2:21][C:15]2[N:14]=[C:13]([C:11]3[S:12][C:8]4[C:7]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=4[N:10]=3)[NH:22][C:16]=2[CH2:17][CH2:18]1)=[O:41]
Reactant: CN(C)C(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)N(C)C)CC4)nc12
Yield: 92.4 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.07 ml N-ethyldiisopropylamine and 0.012 g dimethylcarbamoyl chloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.04 g (92%) 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid dimethylamide as yellow solid; MS (ISP): m/e=457 (M+H+).
Reaction SMILES: [O-]S([C:5](F)(F)F)(=O)=O.[OH:9][C@H:10]1[CH2:15][C@@H:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@:12]([C@@H:26]2[CH2:30][S:29][C:28](=[O:31])[N:27]2[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)([O:24][CH3:25])[CH2:11]1.O[C@H:42]1[CH2:47][C@@H:46](CCCC=C)[O:45][C@:44]([C@@H:55]2[CH2:59]SC(=O)N2CC2C=CC(OC)=CC=2)(OC)[CH2:43]1>>[CH3:25][O:24][C@:12]1([C@@H:26]2[CH2:30][S:29][C:28](=[O:31])[N:27]2[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[CH2:11][C@H:10]([O:9][C:46](=[O:45])/[CH:47]=[C:42](/[CH3:5])\[CH2:43][CH2:44][CH:55]=[CH2:59])[CH2:15][C@@H:14]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:13]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@@H](O)C[C@@H](CCc3ccccc3)O2)cc1
Reactant: C=CCCC[C@@H]1C[C@H](O)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Reactant: O=S(=O)([O-])C(F)(F)F
Product: C=CCC/C(C)=C\C(=O)O[C@@H]1C[C@@H](CCc2ccccc2)O[C@@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)C1

Procedure:
Triflate formation using the method shown in Example 22, with the modification that (R)-4-((2R,4S,6R)-4-hydroxy-2-methoxy-6-phenethyl-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one is substituted for (R)-4-((2R,4S,6R)-4-hydroxy-2-methoxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, followed by triflate displacement using the method shown in Example 23, affords the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:37]3[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=3)=[N:8][N:9]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1ccc(Cn2nc(OS(=O)(=O)C(F)(F)F)c3c(OC)nccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(-c3ccc(S(N)(=O)=O)cc3)c3c(OC)nccc32)cc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution of 4-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (100 mg) in DMF (4 mL)/water (0.30 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (102 mg), tetrakis(triphenylphosphine)palladium(0) (27.7 mg) and potassium carbonate (66.2 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (45.0 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6](=O)[C@H:7]([CH3:12])[C@H:8]([CH3:11])[CH2:9][CH3:10])[CH3:2].Cl.[O:16]([NH2:18])[CH3:17].C([O-])(=O)C.[Na+].CC(OC)(C)C>CCO.O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6](=[N:18][O:16][CH3:17])[C@H:7]([CH3:12])[C@H:8]([CH3:11])[CH2:9][CH3:10])[CH3:2]
Reactant: CCOC(=O)CC(=O)[C@H](C)[C@H](C)CC
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: COC(C)(C)C
Solvent: O
Product: CCOC(=O)CC(=NOC)[C@H](C)[C@H](C)CC
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.4 %

Procedure:
(4R,5R)-4,5-Dimethyl-3-oxo-heptanoic acid ethyl ester (21.23 g, 106 mmol) was dissolved in 200 mL of EtOH and added to 10.6 g (127 mmol) of methoxylamine-HCl and 10.6 g (127 mmol) of sodium acetate solids. The slurry was stirred at room temperature for 48 hours. MTBE (200 mL) and 100 mL of water were added, and the resulting phases were separated. The organic phase was washed with 100 mL of water and was evaporated to yield a two-phase mixture. Hexanes (100 mL) were added and the phases were separated. The aqueous phase was extracted with 50 mL of hexanes and the combined organic phases were washed with 50 mL of water, dried over magnesium sulfate, and evaporated to give 21.24 g (87.4% yield) of the titled compound as a clear yellow oil: 1H NMR (CDCl3, 399.77 MHz) δ 0.84-0.88 (m, 6H), 1.07 (d, J=7.1 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 1.4-1.6 (m, 2H), 2.24 (m, 1H), 3.08 (d, J=15.8 Hz, 1H), 3.19 (d, J=15.8 Hz, 1H), 3.80 (s, 3H), 4.10-4.2 (m, 3H). Low resolution mass spec: nominal m/e calc'd for C12H23NO3 (M+H)+: 230. Found: m/e 230.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](=[CH:13]\[C:14]2C=CC=CC=2)/[C:10](O)=O)[CH:5]=[CH:6][C:7]=1[OH:8].CN(C([O:27][N:28]1N=N[C:30]2[CH:31]=[CH:32][CH:33]=N[C:29]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.N[OH:55]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:33][C:32](/[CH:31]=[CH:30]/[C:29]([NH:28][OH:27])=[O:55])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(O)/C(=C/c1ccccc1)c1ccc(O)c(Cl)c1
Reactant: NO
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/c1ccc(-c2ccc(O)c(Cl)c2)cc1)NO
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 9.7 %

Procedure:
205 mg (0.75 mmol) of E-3-chloro-4-hydroxyphenylcinnamic acid were dissolved under nitrogen in 7.5 ml of DMF, then 285 mg (0.75 mmol) of HATU and 97 μL (0.56 mmol) of DIPEA were added and the solution thus obtained was kept under stirring at room temperature for 2 min. After addition of hydroxylamine hydrochloride (261 mg, 3.75 mmol), the mixture was stirred at room temperature for 2 days. DMF was removed under reduced pressure and the residue was washed with water to obtain, after filtration, 140 mg of a crude product. Purification by flash chromatography on reverse phase ((LiChroprep RP-18, MERCK) using as eluent water/methanol 1:1 and crystallization from diethyl ether afforded 21 mg of the title compound as a white solid. M.p. 172-175° C. Rf=0.16 (RP18 MERCK, H2O/MeOH 1:1).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH:13]([N+:15]([O-])=O)[CH2:12][C:11]2=[O:18])[CH:7]=[CH:6][C:5]=1[N:19]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:20]1=[O:26].[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:15][CH:13]1[CH2:14][N:10]([C:8]2[CH:7]=[CH:6][C:5]([N:19]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:20]3=[O:26])=[C:4]([CH3:3])[CH:9]=2)[C:11](=[O:18])[CH2:12]1.[F:30][C:29]([F:32])([F:31])[C:27]([O-:33])=[O:28]
Reactant: Cc1cc(N2CC([N+](=O)[O-])CC2=O)ccc1N1CCCCOC1=O
Reactant: O=C(O)C(F)(F)F
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(N2CC(N)CC2=O)ccc1N1CCCCOC1=O
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
36 mg (150 μmol) nickel(II)chloride-hexahydrate are dissolved in 2 ml of methanol by treatment with ultrasound and combined with 15 mg (396 μmol) sodium borohydride. 100 mg (300 μmol) of 3-[2-methyl-4-(4-nitro-2-oxo-pyrrolidin-1-yl)-phenyl]-[1,3]-oxazepan-2-one are dissolved in 2 ml of methanol and added in two batches to the reaction solution. After the first quantity has been added a further 21 mg (555 μmol) sodium borohydride are put in. Then the remaining solution of the nitro compound is added in sequence followed by another 21 mg (555 μmol) of sodium borohydride. The mixture is then stirred for five hours at ambient temperature, acidified with TFA and purified by chromatography through reversed phase HPLC.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[N+:30]([C:33]1[CH:46]=[CH:45][C:36]([C:37]([O:39][C@H:40]2[CH2:44][CH2:43][NH:42][CH2:41]2)=[O:38])=[CH:35][CH:34]=1)([O-:32])=[O:31]>C(#N)C>[N+:30]([C:33]1[CH:46]=[CH:45][C:36]([C:37]([O:39][C@H:40]2[CH2:44][CH2:43][N:42]([CH2:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)[CH2:41]2)=[O:38])=[CH:35][CH:34]=1)([O-:32])=[O:31]
Reactant: O=C(O[C@H]1CCNC1)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCN2CC[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 90 °C

Procedure:
4-Methoxyphenethyl tosylate (1.24 g, 4.05 mmol), sodium carbonate (430 mg, 4.06 mmol) and sodium iodide (40 mg, 0.26 mmol) were added to a solution of (S)-3-(4-nitrobenzoyloxy)pyrrolidine (799 mg, 3.38 mmol) in acetonitrile (40 ml), and they were heated under reflux at 90° C. for 3 hours. The insoluble material was removed by the filtration. The insoluble material was washed with ethyl acetate, and the wash solution was combined with the filtrate. The solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1) and then with a mixture of the same solvents (1:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-3-(4-nitrobenzoyloxy)-1-(4-methoxy-phenethyl)pyrrolidine in the form of a light yellow oil (1.00 g, 80%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9](#[N:11])[CH3:10].[CH3:12][NH:13][C:14]([C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](OC)=O)[CH:19]=[CH:20][CH:21]=1)=[O:15].Cl.[NH2:29][NH2:30]>O1CCCC1.C(O)C>[NH2:11][C:9]1[NH:30][N:29]=[C:24]([CH2:23][CH2:22][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=2)[C:14]([NH:13][CH3:12])=[O:15])[CH:10]=1
Reactant: CC#N
Reactant: NN
Reactant: CNC(=O)c1cccc(CCC(=O)OC)c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(CCc2cc(N)[nH]n2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 13.6 %

Procedure:
1.8M LDA in THF (30.0 mL, 54.00 mmol) was added to tetrahydrofuran (60 mL) and cooled to −78° C. Acetonitrile (2.82 mL, 54.00 mmol) was added drop-wise over 15 mins. A solution of methyl 3-(3-(methylcarbamoyl)phenyl)propanoate (2.99 g, 13.5 mmol) in tetrahydrofuran (10 ml) was added. The resulting mixture stirred at −78° C. for 10 mins. The reaction mixture was warmed to 5° C. and stirred for 30 mins, hydrazine hydrochloride (3.70 g, 54.00 mmol) and ethanol (60.0 mL) were added and the reaction mixture heated at 80° C. for 18 h. The reaction mixture was cooled and evaporated to dryness. The residue was dissolved in methanol (50 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH fractions were evaporated to dryness to afford an oil. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 3-(2-(5-amino-1H-pyrazol-3-yl)ethyl)-N-methylbenzamide (0.450 g, 13.64%) as a yellow oil.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12](=[O:14])[CH3:13])[CH:7]=[C:6]([CH3:15])[C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=2)[CH:17]=1>CO>[OH:29][CH2:28][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:18]2[CH:17]=[C:16]([C:5]3[C:4]([CH3:3])=[CH:9][C:8]([O:10][CH2:11][CH:12]([OH:14])[CH3:13])=[CH:7][C:6]=3[CH3:15])[CH:21]=[CH:20][CH:19]=2)=[CH:31][CH:30]=1
Reactant: CC(=O)COc1cc(C)c(-c2cccc(COc3ccc(C=O)cc3)c2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(OCC(C)O)cc(C)c1-c1cccc(COc2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In an atmosphere of nitrogen, sodium borohydride was added to a methanol solution of 4-{[2′,6′-dimethyl-4′-(2-oxopropoxy)biphenyl-3-yl]methoxy}benzaldehyde under ice-cooling, followed by stirring at room temperature for 2 hours to obtain 1-[(-3′-{[4-(hydroxymethyl)phenoxy]methyl}-2,6-dimethylbiphenyl-4-yl)oxy]propan-2-ol. By adding chloroform and manganese dioxide to the resulting compound and stirring at 60° C. for 5 hours, 4-{[4′-(2-hydroxypropoxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy}benzaldehyde was obtained.