Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:20]([CH3:21])=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=[C:17]([Br:25])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11].[BH4-].[Na+]>CCO.C1COCC1>[Br:1][C:2]1[C:20]([CH3:21])=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=[C:17]([Br:25])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:8]([OH:13])=[C:9]([CH2:10][OH:11])[CH:12]=1
Reactant: Cc1c([N+](=O)[O-])cc(Br)c(Oc2cc(C=O)c(O)c(C(C)C)c2)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c([N+](=O)[O-])cc(Br)c(Oc2cc(CO)c(O)c(C(C)C)c2)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
5-(2,6-Dibromo-3-methyl-4-nitrophenoxy)-2-hydroxy-3-isopropylbenzaldehyde of Part 8D (100 mg, 0.21 mmol) and NaBH4 (9.0 mg, 0.23 mmol) was dissolved in a mixture of EtOH and THF (3 mL, 2:1) at room temperature. After 1.5 hours of stirring at room temperature, the reaction mixture was concentrated and the residue suspended in CHCl3. The suspension was washed with 1N HCl and the two phases were separated with a phase separator (IST) before concentration of the organic phase. The residue was purified on column (silica gel, gradient elution: n-heptane/EtOAc from 1:0 to 7:3) to give 85 mg (85%) of 4-(2,6-dibromo-3-methyl-4-nitrophenoxy)-2-hydroxymethyl-6-isopropylphenol as a light yellow foam.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([CH3:25])([CH3:24])[C:21](O)=[O:22])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.Cl.[CH:47]12[NH:53][CH:50]([CH2:51][CH2:52]1)[CH2:49][CH2:48]2>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([CH3:24])([CH3:25])[C:21]([N:53]3[CH:47]4[CH2:52][CH2:51][CH:50]3[CH2:49][CH2:48]4)=[O:22])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:27]=[C:28]([CH3:33])[CH:29]=[C:30]([CH3:32])[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CC2CCC1N2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2CCNC(=O)OC(C)(C)C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 2-[3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid (856 mg in 8.0 mL methylene chloride) at 0° C. was added 310 mg of 1-hydroxybenzotriazole (HOBt)followed by 400 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and the mixture stirred at low temperature for 90 minutes. At this time, a solution of 7-aza-bicyclo[2.2.1]heptane hydrochloride (632 mg in a mixture of 2.0 mL methylene chloride and 0.66 mL triethylamine) was added and the mixture warmed to room temperature. The reaction was quenched after 24 hours by dilution with methylene chloride and washing with half-saturated brine. The combined organics were dried over magnesium sulfate and the concentrate purified by flash chromatography on silica gel (hexane:ethyl acetate, 70:30; then 60:40; then 50:50; then 40:60) to give the title compound (736 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.[F:15][CH2:16][CH:17](O)[CH2:18][F:19].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>[F:15][CH2:16][CH:17]([N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1)[CH2:18][F:19]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: OC(CF)CF
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(C(CF)CF)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of Pyrazole-4-boronic acid pinacol ester (6.6 g, 34 mmol, 1 eq.) in dry THF (150 mL) was added 1,3-Difluoro-2-propanol (5.1 g, 51 mmol, 1.5 eq.) followed by triphenylphosphine (13.5 g, 51 mmol, 1.5 eq.) and Diisopropyl azodicarboxylate (10.5 g, 51 mmol, 1.5 eq.) at 0° C. under nitrogen atmosphere. After the addition, the reaction mixture was stirred at RT for 48 h. The reaction mixture was concentrated under vacuum and the residue was solubilized in EtOAc, washed with water (three times), dried over sodium sulfate, filtered and concentrated. The crude product was redissolved in EtOAc and Pet. Ether was added. The precipitate obtained was filtered off and the filtrate concentrated under reduced pressure to give the title compound as a oil (contaminated with triphenyl phosphine oxide).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: C#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 609 %

Procedure:
A mixture of 3-hydroxy-1-ethynylbenzene (4.36 g, 37 mmol), benzylbromide (6.95 g, 4.1 mmol) and K2CO3 (10.2 g, 7.4 mmol) in acetanitrile (50 ml) is stirred at room temperature for 24 hr. The insoluble material is removed by filtration and filtrate is concentrated. The crude material is purified by flash chromatography (silica gel, hexane/EtOAc: 95/5) to afford the title compound as a clear oil 5.2 g (68%).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:16]#[N:17])[CH3:2].COC1C=CC(/C=[C:33]2/[C:34]([NH:36][C:37]([S:39]/2)=[NH:38])=[O:35])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:38][C:37]1[S:39]/[C:33](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([C:16]#[N:17])=[C:4]3[S:3][CH2:1][CH3:2])/[C:34](=[O:35])[N:36]=1
Reactant: CCSc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCSc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 38 was used, starting from 4-ethylsulfanyl-6-formyl-quinoline-3-carbonitrile (example 54b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-ethylsulfanyl-quinoline-3-carbonitrile. LC-MS m/e 341 (MH+).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:17]2([C:23]([O-:25])=[O:24])[CH2:21][CH2:20][C:19](=[O:22])[O:18]2)[C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[C:28]([O:34][CH2:35]Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].O>CN(C=O)C>[O:1]([CH2:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:17]2([C:23]([O:25][CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:24])[CH2:21][CH2:20][C:19](=[O:22])[O:18]2)[C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(COc1ccccc1)N[C@H]1CON(C2(C(=O)[O-])CCC(=O)O2)C1=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)C1(N2OC[C@H](NC(=O)COc3ccccc3)C2=O)CCC(=O)O1

Procedure:
Compound (28b) was dissolved in DMF, and chloromethyl pivalate was added to the solution, followed by stirring. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was concentrated, and hexane was added to the residue. The mixture was subjected to decantation twice and to further decantation (twice) with petroleum benzine. The residue was dried through a vacuum pump to give the subject Compound (28c).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)C=C1CCN(Cc2cccnc2OC)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCN(Cc2cccnc2OC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.6 g of ethyl 2-[1-[(2-methoxy-3-pyridyl)methyl)hexahydro-4-pyridinylidene]acetate and 380 mg of 10% palladium-carbon powder (water-containing product) were suspended in 20 ml of ethyl acetate. After replacing the atmosphere of a container with hydrogen, the mixture was stirred at room temperature under normal pressure for one hour. The reaction solution was filtered, and the filtrate was evaporated, to give the title compound as a yellow oil (quantitatively).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=O)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:35].[CH3:37][NH:38][CH3:39].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][N:38]([CH3:39])[CH3:37])=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:14]=1[CH3:35]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and dimethylamine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 18 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the title compound (0.03 g, 26%). LCMS: 518.25 (M+1)+; HPLC: 89.16% (@ 254 nm) (Rt; 3.982; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.81 (s, 1H), 8.18 (t, 1H), 8.08 (d, 1H, J=8 Hz), 7.52 (d, 1H, J=8 Hz), 7.43 (s, 1H), 7.26 (s, 1H), 5.86 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.83-3.86 (m, 4H), 3.32 (2H merged in solvent peak), 3.03 (m, 1H), 2.64 (s, 3H), 2.50 (3H merged in solvent peak), 2.40 (bs, 3H), 2.24 (s, 3H), 2.21 (s, 3H), 2.10 (s, 3H), 1.60 (bs, 4H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=3)=[N:11]2)=[CH:6][CH:5]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O>O1CCCC1>[F:27][C:2]([F:1])([F:26])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][OH:24])[CH:18]=[CH:19][CH:20]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
In a 500 mL round bottomed flask 3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoic acid (CA13) (5.68 g, 15.1 mmol) was dissolved in tetrahydrofuran (151 mL). The reaction was cooled in an ice water bath and placed under inert atmosphere. Aluminum(III) lithium hydride (2.0 M in tetrahydrofuran, 15.8 mL, 31.6 mmol) was added dropwise. The reaction was allowed to gradually warm to room temperature and stir overnight. The reaction was cooled in an ice bath and water (1.2 mL) was added dropwise to quench excess aluminum(III) lithium hydride, the reaction mixture was allowed to stir for 1 hour. Then sodium hydroxide (15 wt %, 1.2 mL) was added dropwise. The reaction was allowed to stir for 1 hour. Then water (3.6 mL) was added. The resulting precipitate was removed via filtration. The filtrate was concentrated to give a yellow solid (5.20 g). The solid was purified by flash column chromatography using 0-60% ethyl acetate/hexanes as eluent providing the title compound as a white solid (4.01 g, 72%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.18-8.04 (m, 2H), 7.99-7.89 (m, 2H), 7.68-7.57 (m, 2H), 7.43 (t, J=7.6 Hz, 1H), 7.32 (dt, J=7.7, 1.5 Hz, 1H), 4.51 (t, J=5.2 Hz, 1H), 3.45 (td, J=6.4, 5.1 Hz, 2H), 2.71 (dd, J=8.8, 6.7 Hz, 2H), 1.87-1.70 (m, 2H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 364 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>COCCO>[CH2:19]([O:12][C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCO
Product: CC(C)(C)c1cc(OCc2ccccc2)ccc1O

Procedure:
To a stirred solution of t-butyl hydroquinone (1.0 Kg) in 2-methoxy ethanol (2.0 L), was charged K2CO3 (2.0 Kg) portionwise under nitrogen atmosphere and the mixture refluxed. Benzyl chloride (0.762 L) was added dropwise at reflux temperature and heated further for 1.5 hr. The progress of the reaction was monitored on TLC. The reaction mixture was cooled and added DM Water (6.0 L). The uppermost oily layer was separated, dissolved in ethyl acetate (3.4 L), and washed with DM water (3.4 L×3). The uppermost oily layer was separated, dried over sodium sulfate and evaporated to dryness to give the crude title compound (1.5 Kg). The crude product was employed in the next step without further purification,
Reaction SMILES: Cl.[N+:2]([O-:11])([O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:3].C(N(CC)CC)C.[C:19](=O)([O:30]C1C=CC([N+]([O-])=O)=CC=1)[O:20][C@@H:21]1[CH2:25][O:24][C@@H:23]2[C@H:26]([OH:29])[CH2:27][O:28][C@H:22]12>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N+:2]([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:19]([O:20][C@@H:21]2[CH2:25][O:24][C@@H:23]3[C@H:26]([OH:29])[CH2:27][O:28][C@H:22]23)=[O:30])[CH2:7][CH2:6]1)([O-:11])=[O:3]
Reactant: O=[N+]([O-])OC1CCNCC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O)N1CCC(O[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of piperidin-4-yl nitrate hydrochloride (0.620 g, 3.40 mmol), triethylamine (0.567 ml, 4.07 mmol) and 4-dimethylaminopyridine (0.083 g, 0.680 mmol) in DCM (23 ml), (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-nitrophenyl carbonate (1.06 g, 3.40 mmol) was added; the mixture was stirred at room temperature for 18 hrs. Then the mixture was diluted with DCM and washed with a 5% solution of sodium dihydrogen phosphate (2×30 ml) and brine (1×30 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 30 to 100%), affording the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:38]1([CH3:50])[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[C:39]=1[S:46](Cl)(=[O:48])=[O:47].[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[CH3:50][C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[C:39]=1[S:46]([N:6]([CH2:5][C:4]1[CH:21]=[CH:22][C:23]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[C:2]([CH3:1])[CH:3]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1)(=[O:47])=[O:48]
Reactant: Cc1cc(CNc2ccc(OCCN3CCCC3)cc2)ccc1OC1CCCCO1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(OC3CCCCO3)c(C)c2)c2ccc(OCCN3CCCC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.1 %

Procedure:
To a solution of [3-methyl-4-(tetrahydro-pyran-2-yloxy)-benzyl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.062 g, 0.15 mmol) in 0.4 mL methylene chloride was added triethylamine (0.06 mL, 0.45 mmol) and 2-mesitylene sulfonyl chloride (0.066 g, 0.3 mmol). The reaction mixture was stirred at room temperature for 24 hr. PS-isocyanate resin (0.050 g) and PS-trisamine resin (0.050 g) were added and the reaction mixture was stirred for 2 hr. at room temperature. The resin was filtered off with the aid of methylene chloride. The filtrate was concentrated to give the title compound of Step A (0.089 g). MS 593.3 (M+1)+
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>[H-].[Na+]>[C:9]([O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:10])[CH2:8][C:7]([CH3:6])=[O:11]
Reactant: C=C1CC(=O)O1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Product: CC(=O)CC(=O)OCC1CC1
Yield: 92.8 %

Procedure:
0.1 g of sodium hydride (50%) was added to 25 g of cyclopropylmethanol and then 29 g of diketene was added dropwise thereto at a temperature of 50° to 60° C. with stirring. After completion of the addition, the mixture was heated at that temperature for 1 hour. The resulting oil was distilled under reduced pressure to obtain 50 g (93% yield) of cyclopropylmethyl acetoacetate as a colorless oil having a boiling point of 78° C. (4 mmHg).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([Cl:23])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCCCCOc1ccccc1
Product: O=C(Cl)CCCCCCCCCCOc1ccccc1
Reaction time: 8 h

Procedure:
250 mg of 11-phenoxy undecanoic acid (commercial) is mixed with 2 ml of pure thionyl chloride and the whole is left overnight at ambient temperature. In this way 265 mg of expected product is obtained.
Reaction SMILES: CO[C:3](=[O:22])[CH2:4][CH2:5][C:6](=[O:21])[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:9]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:10]2[CH:11]=[C:12]([CH3:13])[N:8]([CH:7]3[C:3](=[O:22])[CH2:4][CH2:5][C:6]3=[O:21])[N:9]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)CCC(=O)Cn1nc(-c2ccc(Cl)cc2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(Cl)cc2)nn1C1C(=O)CCC1=O
Temperature: 200 °C
Yield: 50.4 %

Procedure:
5-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-4-oxo-pentanoic acid methyl ester (1.7 g, 5.5 mmol) was dissolved in dimethylformamide (16 ml) and anhydrous potassium carbonate (3 g, 22 mmol) added. The mixture was then heated to 200° C. for 10 mins in the microwave (using “normal” absorbtion). The reaction was reduced in vacuo, and partitioned between 2 M hydrochloric acid (50 ml) and dichloromethane (100 ml). The layers were separated, and the aqueous layer saturated with sodium chloride and extracted with dichloromethane (100 ml). The organics were combined, dried over magnesium sulfate and the solvent removed in vacuo. The reaction was then purified by column chromatography (using DCM:EtOAc:AcOH (9:1:0.01%) to (3:7:0.01%)) to give 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-cyclopentane-1,3-dione (0.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=Cc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
To a solution of 2-hydroxybenzaldehyde (226 mg) and 1-(2-bromoethoxy)-4-nitrobenzene (500 mg) in N,N-dimethylformaldehyde (5 mL) was added potassium carbonate (281 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water (20 mL), and the mixture was extracted with ethyl acetate (20 ml). The extract was washed successively with 0.5M aqueous hydrochloric acid solution, 1M aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-(2-(4-nitrophenoxy)ethoxy)benzaldehyde (560 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([C:20]#[N:21])=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].[OH-:24].[K+]>O.CC(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([C:20]([NH2:21])=[O:24])=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C#N
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C(N)=O

Procedure:
A solution of 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (727 mg, 2.28 mmol) and KOH (767 mg, 13.7 mmol) in H2O (7.70 mL) and i-PrOH (11.55 mL) was subjected to microwave irradiation (300 W 130° C., 4 h) in a sealed tube. The reaction mixture was concentrated in vacuo to remove the i-PrOH. The aqueous slurry obtained was diluted with water (50 mL) and extracted with EtOAc (50 mL). The organic extract was dried (Na2SO4) and concentrated in vacuo to afford 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carboxamide. The aqueous layer was acidified with concentrated HCl and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carboxylic acid as a colorless solid. 1H NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.14 (d, J=8.1 Hz, 1H), 7.04 (s, 1H), 6.77 (d, J=8.1, 1H), 3.68 (s, 3H), 2.84 (septet, J=6.7 Hz, 1H), 1.19 (d, J=6.7 Hz, 6H).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[CH2:5]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=O)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:13][CH2:14]1
Reactant: O=C1CCN(Cc2ccccc2)c2ccccc21
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCN(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methoxylamine hydrochloride (0.74 g, 8.9 mmol) was added to a solution of Example 15C (1.92 g, 8.1 mmol) in pyridine (20 mL) and stirred overnight at ambient temperature. The mixture was concentrate under reduced pressure, ethyl acetate (200 mL) was added, and the organic layer was washed twice with water (200 mL) and brine, dried over sodium sulfate, filtered, and concentrate under reduced pressure. The residue was chromatographed on silica gel eluting with 0-20% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 2.88 (t, J=6.44 Hz, 2H), 3.29 (t, J=6.44 Hz, 2H), 3.97 (s, 3H), 4.47 (s, 2H), 6.65 (d, J=8.14 Hz, 1H), 6.70 (t, J=7.46 Hz, 1H), 7.13 (td, J=7.80, 1.70 Hz, 1H), 7.31 (m, 5H), 7.92 (dd, J=7.80, 1.70 Hz, 1H). MS (DCI) m/z 267.11 (M+H)+.