Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=O)[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:23]=2[N:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:19][C:20]3[S:21][C:22]4[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[O:18])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc2nc(N)sc2c1
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2nc(NC(=O)c3nnn(Cc4ccc(Cl)c(Cl)c4)c3C)sc2c1
Temperature: 45 °C
Reaction time: 72 h
Yield: 9.6 %

Procedure:
A mixture of 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) (0.1 g, 0.35 mmol), 2-amino-6-methoxybenzothiazole (0.062 g, 0.35 mmol), HATU (0.082 g, 0.45 mmol) and DIPEA (85 μL, 0.45 mmol) in DMF (5 mL) was stirred at 45° C. for 3 days. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with DCM/MeOH (99/1) to give after trituration in diisopropyl ether, the title compound as a white solid (15 mg, 10%). HRMS calculated for C19H15Cl2N5O2S (M+H)+ 448.0402, found: 448.0403, Rt: 3.31 min. MP: 225° C.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[C:21]1(=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[NH:22]1>>[O:31]=[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]1[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Product: CN(C(=O)Oc1ccc(CCN2C(=O)c3ccccc3C2=O)cc1)c1ccccc1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and isoindole-1,3-dione. NMR (400 MHz; CDCl3): δ 2.98 (t, 2H), 3.41 (br s, 2H), 3.89 (t, 3H), 7.04 (br d, 2H), 7.20-7.40 (m, 7H), 7.68-7.71 (m, 2H), 7.80-7.83 (m, 2H); HPLC-MS: m/z=401.1 (M+1); Rt=4.41 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:35])[CH:9]([C:23]1[NH:24][C:25](=[O:34])[C:26]([OH:33])=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:28]=1)[CH2:10][CH2:11][C:12]([CH3:22])([CH3:21])[CH2:13][O:14]C1CCCCO1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([O:5][C:6]([N:8]([CH3:35])[CH:9]([C:23]1[NH:24][C:25](=[O:34])[C:26]([OH:33])=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:28]=1)[CH2:10][CH2:11][C:12]([CH3:22])([CH3:21])[CH2:13][OH:14])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1nc(C(CCC(C)(C)COC2CCCCO2)N(C)C(=O)OC(C)(C)C)[nH]c(=O)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1nc(C(CCC(C)(C)CO)N(C)C(=O)OC(C)(C)C)[nH]c(=O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the crude methyl 2-[1-[(tert-butoxycarbonyl)(methyl)amino]-4,4-dimethyl-5-(tetrahydro-2H-pyran-2-yloxy)pentyl]-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (32 g) and 1 g of p-toluenesulfonic acid monohydrate was dissolved in methanol (100 mL) and stirred at room temperature for 2 hours. The reaction was quenched with 3 mL of saturated NaHCO3 and concentrated. The residue was taken up in 500 mL of EtOAc, washed with saturated NaHCO3 and dried over Na2SO4. Removal of solvents under reduced pressure gave the title product as a brown foam: MS (ES+): 314.1 (M+H).
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[Cl:10][CH2:11][C:12](Cl)=[O:13].[CH3:15][N:16]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:27][CH3:28])[CH:20]=[CH:19][C:17]1=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:15][N:16]1[C:26]2[C:21](=[C:22]([C:12](=[O:13])[CH2:11][Cl:10])[CH:23]=[CH:24][C:25]=2[O:27][CH3:28])[CH:20]=[CH:19][C:17]1=[O:18]
Reactant: O=C(Cl)CCl
Reactant: COc1cccc2ccc(=O)n(C)c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)CCl)c2ccc(=O)n(C)c12
Temperature: 0 °C

Procedure:
40 ml of nitrobenzene and 12 ml of monochloroacetyl chloride (V) were added to 7.4 g of 1-methyl-8-hydroxycarbostyril (VI), and 20 g of aluminum chloride was added slowly to the mixture while cooling with ice-water followed by allowing the mixture to react at a temperature of 60° C. for 18 hours while stirring. The reaction mixture was then poured into 500 ml of ice-water to precipitate the product. The precipitate was filtered, washed with diethyl ether and recrystallized from a mixture of ethanol and dimethylformamide (1:1 by volume) to obtain 2.8 g of white amorphous 1-methyl-5-chloroacetyl-8-hydroxycarbostyril (IV) having a melting point of 287° to 289° C. (with decomposition). The product thus obtained was confirmed by elemental analysis and IR and NMR spectral analyses.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)=[C:10]([C:26]#[N:27])[CH:9]=1)=[O:6])C.[OH-].[Na+]>CCO>[C:26]([C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]([OH:28])=[O:3])[CH:13]=[C:12]([CH3:14])[C:11]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:23]([CH3:24])[CH3:25])[CH:17]=1)#[N:27]
Reactant: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc(O)c(C(C)C)c2)c(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(NC(=O)C(=O)O)cc(C#N)c1Oc1ccc(O)c(C(C)C)c1
Yield: 8.8 %

Procedure:
A solution of N-[3-cyano-4-(4-hydroxy-3-isopropyl-phenoxy)-5-methyl-phenyl]-oxamic acid ethyl ester (110 mg) and 1N aqueous sodium hydroxide (0.6 mL) in EtOH (1 mL) was stirred at ambient temperature for 10 min, partitioned between ethyl acetate/1N aqueous hydrochloric acid, the organic layer washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a colorless solid (9 mg). MS: 353.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][O:14]2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH:15]12[CH2:16][NH:8][CH2:9][CH:10]1[NH:11][CH2:12][CH2:13][O:14]2
Reactant: c1ccc(CN2CC3NCCOC3C2)cc1
Agent: [Pd]
Solvent: CO
Product: C1COC2CNCC2N1

Procedure:
7.2 g (33 mmol) of 8-benzyl-2-oxa-5,8-diazabicyclo-[4.3.0]nonane are hydrogenated in 400 ml of methanol with 2.5 g of palladium-on-active charcoal (10% of Pd) under 50 bar at 100° C. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][C:10](=[O:12])[CH3:11]
Reactant: Cc1ccc(C)c(N)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(C)ccc1C
Reaction time: 4 h

Procedure:
To a stirred solution of 2,5-dimethylaniline (5.30 g) and 4-dimethylaminopyridine (6.41 g) in dichloromethane (90 ml) was added acetic anhydride (4.13 ml) under ice-cooling, and the mixture was stirred for 4 hours. The reaction mixture was washed with 1N hydrochloric acid and a saturated aqueous sodium bicarbonate solution subsequently, and dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 2′,5′-dimethylacetanilide (6.09 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@H:14]([OH:18])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CN(C1C=CN=CC=1)C>[C:25]([O:18][C@@H:14]([CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:15]([OH:17])=[O:16])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(NCC[C@H](O)C(=O)O)OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(NCC[C@H](OC(=O)c1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 51 %

Procedure:
To a stirring solution of (S)-4-(benzyloxycarbonylamino)-2-hydroxybutanoic acid (1, 612 g, 2.41 mol) in THF (6 L) at 0° C. was added DMAP (2.4 g) and pyridine (196 mL, 2.41 mol). After stirring for 20 minutes, benzoyl chloride (280 mL) was added slowly and the reaction was allowed to stir overnight at room temperature. The resulting precipitate was filtered and the filtrate was acidified with 1 M citric acid (1 L). The organic solvent was removed by rotary evaporation and the desired product was extracted with EtOAc (2×2 L). The combined organic layers were washed with 1 M citric acid (1 L), brine (1 L) and then dried over MgSO4. Solvent removal under vacuum resulted in a viscous oil, which was purified on a 6-inch reverse-phase HPLC column to yield (S)-2-(benzoyloxy)-4-(benzyloxycarbonylamino)butanoic acid (2) as a non-flowing viscous oil (439 g, 51% yield).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]([NH2:22])=[O:21].C([O:25][C:26](=O)[CH2:27][C:28]([CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1)=O)C>CC(O)=O>[O:25]=[C:26]1[CH:27]=[C:28]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[N:6]2[N:5]=[C:4]([C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:11][CH:12]=3)[C:3]([C:20]([NH2:22])=[O:21])=[C:2]2[NH:1]1
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Solvent: CC(=O)O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c(C3CCNCC3)cc(=O)[nH]c12
Temperature: 90 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (412 mg, 1.4 mmol) and tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (420 mg, 1.4 mmol) in HOAc (20 mL) was stirred at 90° C. for 16 hr. The solvent was removed under vacuum, and the residue was partitioned between aq. NaHCO3 and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by Pre-HPLC eluting from 25% to 90% CH3CN in 0.1% TFA in H2O. Fractions containing the desired product were combined and lyophilized overnight to afford 5-oxo-2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide (0.3 g, 50%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.71 (br s, 1H), 8.68-8.65 (m, 1H), 8.42-8.39 (m, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.47-7.41 (m, 2H), 7.22-7.18 (m, 1H), 7.14-7.09 (m, 4H), 5.72 (s, 1H), 3.50-3.35 (m, 2H), 3.17-3.06 (m, 1H), 3.01-2.87 (m, 2H), 2.15-2.05 (m, 2H), 1.83-1.72 (m, 2H). MS (ESI) m/e [M+1]+ 430.1.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:13](=[O:30])[N:12]2[CH2:31][C:32]([O:34]C)=[O:33])[CH:7]=[C:8]([F:10])[CH:9]=1>C1COCC1.O>[C:20]([O:19][C:17]([N:15]1[CH2:16][CH:11]([C:6]2[CH:5]=[C:4]([F:3])[CH:9]=[C:8]([F:10])[CH:7]=2)[N:12]([CH2:31][C:32]([OH:34])=[O:33])[C:13](=[O:30])[CH:14]1[CH:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)CN1C(=O)C(C2CCOCC2)N(C(=O)OC(C)(C)C)CC1c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C1C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12 mg (0.48 mmol) lithium hydroxide were added to 0.20 g (0.43 mmol) tert-butyl 5-(3,5-difluorophenyl)-4-(2-methoxy-2-oxoethyl)-3-oxo-2-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (isomer mixture 1.1) in 5 ml THF and 1 ml of water. The mixture was stirred for 2 h at RT and then evaporated to dryness.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18]Br>O1CCCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: COC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of methyl 4-hydroxybenzoate (366 mg, 2.41 mmol) and sodium hydride (116 mg, 60% w/w dispersion in oil, 2.65 mmol) in tetrahydrofuran (12 mL) was added 3,4-dichlorobenzyl bromide (578 mg, 2.41 mmol) and the reaction mixture was stirred at room temperature for 48 hours. The reaction was quenched by addition of methanol (15 mL) and was then evaporated to dryness. The resulting residue was purified by flash column chromatography using ethyl acetate/heptane as eluant. The title compound was isolated as a white solid (750 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([S-:12])#[N:11].[NH4+].BrBr>C(O)(=O)C>[NH2:11][C:10]1[S:12][C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: N#Cc1ccc(N)cc1
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: N#Cc1ccc2nc(N)sc2c1
Temperature: 13.5 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a mixture of 4-aminobenzonitrile (23.6 g, 0.2 mol) and ammonium rhodanate (30.4 g, 0.4 mol) was added glacial acetic acid (600 mL) and the resulting solution was cooled to 13.5° C. on an ice-bath. A mixture of bromine and glacial acetic acid was added drop-wise and slowly. The resulting mixture was stirred for 1 hour at 13.5° C. and filtered. The filter cake was washed with glacial acetic (6×100 mL) and placed in hot water (1000 mL) with stirring. The mixture was filtered and pH of the filtrate was adjusted to 7 with a saturated sodium carbonate solution. The precipitate was isolated and dried to give 19.5 g (56%) of 2-aminobenzothiazole-6-carbonitrile. A mixture of concentrated hydrochloric acid (113 mL) and water (52 mL) was heated at 90° C. while 2-aminobenzothiazole-6-carbonitrile (19 g, 0.108 mol) was added. The mixture was cooled to −5° C. on an ice-bath and a solution of sodium nitrite (7.72 g, 0.112 mol) in water (20 mL) was added drop-wise, keeping the temperature below than 0° C. When addition was complete the mixture was stirred for 0.5 hour and a solution of CuCl2 (16 g) in water (108 mL) was added drop-wise. When addition was complete the mixture was stirred for 10 min, and the ice-bath was removed. Stirring was continued for 2 h and the mixture was cooled to room temperature. The mixture was filtered and the solid was washed to neutrality with water and dried. This afforded 12.8 g (61%) of 2-chlorobenzothiazole-6-carbonitrile. 1H-NMR δ 8.14 (s, 1H), 8.03 (d, 1H), 7.75 (d, 1H).
Reaction SMILES: [CH3:1][NH2:2].O=[C:4]1[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6][CH2:5]1>>[CH3:1][NH:2][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6][CH2:5]1
Reactant: CN
Reactant: N#CC1CCC(=O)CC1
Product: CNC1CCC(C#N)CC1

Procedure:
Following the procedure as described in Example 25, STEP D, methyl amine and 4-oxo-cyclohexanecarbonitrile were reacted to yield 4-methyamino-cyclohexanecarbonitrile as a white solid, as its corresponding hydrochloride salt.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:34])[CH:6]([O:32][CH3:33])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:10][C:9]=1[F:31]>C1COCC1.O>[C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH:6]([O:32][CH3:33])[C:5]([OH:34])=[O:4])=[C:9]([F:31])[CH:10]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)C(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1F)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1F)C(=O)O
Reaction time: 8 h
Yield: 83.2 %

Procedure:
1N aqueous lithium hydroxide solution (1.37 mL) was added to a solution of 3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-propionic acid methyl ester (0.075 g, 0.17 mmol) in THF (2 mL) at room temperature. The reaction mixture was stirred overnight, diluted with water (10 mL), and extracted with diethyl ether (3×20 mL). The aqueous layer was acidified with 1N HCl to pH 1 and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to give 3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-propionic acid as a white solid (60 mg, 83%). 1H-NMR (200 MHz, CDCl3): 7.56–7.29 (m, 7H), 7.18–7.09 (m, 1H), 6.98 (d, 2H, J=8.6), 6.66–6.60 (m, 2H), 4.17 (dt, 4H, J=8.9, 5.9), 4.03 (dd, 1H, J=6.7, 4.8), 3.40 (s, 3H), 3.23–3.14 (m, 1H), 2.97 (dd, 1H, J=14.0, 6.7), 2.26 (q, 2H, J=5.9)ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][C@H:12]2[CH3:28])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C[C:30]([O-])([CH3:32])C.[Na+]>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]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:15][CH2:16][N:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([N:14]4[CH2:32][CH2:30][N:11]([CH3:16])[CH2:12][CH2:13]4)[CH:3]=3)(=[O:10])=[O:9])[C@H:12]([CH3:28])[CH2:13]2)=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:19]=1
Reactant: CC(C)(C)[O-]
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na+]
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(N2CCN(C)CC2)c1
Temperature: 110 °C
Yield: 155.8 %

Procedure:
A mixture of (2R)-1-[(3-bromophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazine (8 g, 16.667 mmol), N-Me-piperazine (2.22 mL, 20 mmol), bis-t-Bu-biphenylphosphine (298.2 mg, 1.0 mmol), tBuONa (2.4 g, 25 mmol) and Pd2(dba)3 (305.2 mg, 0.333 mmol) was mixed and purged with N2. Anhydrous toluene (80 mL) was added and purged with N2 again. The resultant mixture was heated in an oil bath at 110° C. under N2 for 5 hours. After cooling, diluted with EtOAc (100 mL), filtered through a pad of Celite and washed with EtOAc (100 mL). The combined organic layer washed with aq. NaHCO3. The aqueous layer was back extracted with EtOAc (2×50 mL). The combined organic layer was dried over Na2SO4. The crude product was purified on SiO2 gel column eluted with 0-25% MeOH in EtOAc to give the desired product as a light yellow solid (6.5 g, 78%). HRMS: calcd for C23H28F4N4O2S+H+, 501.19418. found (ESI-FTMS, [M+H]1+), 501.1944.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[O:11][CH:12]([CH2:15][CH2:16][OH:17])[C:13]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[O:11][CH:12]([CH2:15][CH2:16][OH:17])[C:13]=1[O:14][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC(CCO)C(O)=C1OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Yield: 58.8 %

Procedure:
A mixture of 1.25 g (5 mmol) of 3-benzyloxy-4-hydroxy-5-(2-hydroxyethyl)-2(5H)-furanone, 15 mL of THF, 871 μL (5.0 mmol) of diisopropylethylamine and 631 μL (5.2 mmol) of benzyl bromide were combined under argon. The reaction mixture was warmed to reflux for 5 hours, and upon cooling, a suspension formed which was poured into 50 mL of 5% aqueous HCl solution and extracted with 100 mL of ether. The ether fraction was separated and sequentially washed with 30 mL of 5% aqueous HCl, 30 mL of H2O, 30 mL of saturated NAHCO3 solution, 30 mL of H2O, 30 mL of brine, dried (MgSO4) and concentrated to a colorless oil. Purification over silica gel using EtOAc/hexanes (2/3) provided 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone as a faint pink colored oil (1.0 g, 60% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[N:8]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1>ClCCl>[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[N:8]2)=[CH:24][CH:25]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1
Reactant: COc1ccc(C2=NN(Cc3ccc(N)cc3)C(=O)CC2)cc1OC
Reactant: O=C(Cl)c1cccnc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C2=NN(Cc3ccc(NC(=O)c4cccnc4)cc3)C(=O)CC2)cc1OC
Reaction time: 1 h

Procedure:
A solution of 3.4 g of 2-(4-aminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, m.p. 184°, and 0.75 ml of pyridine in 100 ml of dichloromethane is treated with 1.4 g of nicotinoyl chloride and subsequently stirred for 1 hour. The solvent is removed and the mixture is worked up in the customary manner. After recrystallization, 2-(4-nicotinoylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one is obtained.
Reaction SMILES: FC(F)(F)C([O-])=O.[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH3+:21].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH2:21]
Reactant: [NH3+]CCOCCOCCCCCCCl
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NCCOCCOCCCCCCCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To one equivalent of the succinimidyl ester of the reporter group in DMF is added 3 equivalence of 2-[2-(6-chlorohexyloxy)-ethoxy]-ethyl-ammonium trifluoro-acetate stock solution, followed by diisopropylethylamine. The reaction is stirred from 8 to 16 hours at room temperature. Purification is accomplished by preparative scale HPLC or silica gel chromatography.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=1>CC(O)=O.CCOC(C)=O.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[N:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)nc1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(OCc2cccc(F)c2)nc1
Temperature: 70 °C
Yield: 87.9 %

Procedure:
A mixture of 13A (132 mg, 0.53 mmol) and Fe powder (238 mg, 4.25 mmol) in HOAc/EtOAc (1/1) (2.4 ml) was heated at 70° C. for 2.5 h. The mixture was cooled to rt, filtered through a 1″ celite pad and rinsed with HOAc/EtOAc (1/1) (4×8 ml). The filtrate was concentrated in vacuo. The residue was diluted with 1N NaOH (25 ml), extracted with EtOAc (2×60 ml) and the combined EtOAc extracts were washed with brine (1×20 ml), dried (MgSO4), filtered and concentrated in vacuo to give 13B (101.7 mg, 78% pure) which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10]([Mg]Cl)[CH3:11]>C1COCC1.[Cl-].[NH4+]>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Br)nc1
Reaction time: 4 h

Procedure:
To a chilled (0° C.) solution of 6-bromopyridine-3-carboxaldehyde (15.0 g, 80.6 mmol) in a 1:1 mixture of ether-toluene (400 mL) is added a 2 M solution of ethylmagnesium chloride (40.0 mL, 80.0 mmol) in THF over a 15 minute period. After 4 hours, the mixture is diluted with saturated aqueous ammonium chloride (300 mL) and the organic layer is separated. The aqueous layer is extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine (2×50 mL), dried over magnesium sulfate, filtered and concentrated. The crude material is passed through a pad of silica gel eluting with dichloromethane-hexanes (0-100%). The material from the pad is purified by silica gel chromatography eluting with EtOAc-hexanes (2:98, then 4:96, then 6:94, then 8:92, then 1:9, then 12:88, then 15:85) to afford 1-(6-bromopyridin-3-yl)-propan-1-ol as an oil.