Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:8][C:9]#[N:10].[C:11]1([CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=3)[O:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(#N)C>[C:11]1([CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:8][C:9]#[N:10])[CH:23]=3)[O:18]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#CCCl
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#CCOc1ccc2c(c1)CCC(c1ccccc1)O2
Temperature: 25 °C

Procedure:
Cesium carbonate (310 mg) and chloroacetonitrile (62 μl) were added into a solution of 2-phenylchroman-6-ol (200 mg) in acetonitrile (3 ml). The resulting mixture was refluxed for 6 hours. The reaction mixture was allowed to cool to room temperature and 1 M HCl-solution was added and it was extracted with ethyl acetate. The combined organic layers were washed with water and saturated NaCl-solution and dried with Na2SO4. The solvents were evaporated under reduced pressure to give (2-phenylchroman-6-yloxy)acetonitrile. 1H NMR (400 MHz, d6-DMSO) δ: 7.44-7.30 (m, 5H), 6.86-6.81 (m, 3H), 5.08 (dd, 1H, J 9.8, 2.2 Hz), 5.07 (s, 2H), 2.97 (ddd, 1H, J −16.9, 10.9, 6.0. Hz), 2.71 (ddd, 1H, J −16.9, 5.0, 3.4 Hz), 2.15 (m, 1H), 1.97 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([F:28])[C:26]=1[F:27])[C:21](Cl)=[O:22]>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([F:28])[C:26]=1[F:27])[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:22]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cc(F)c(F)c(F)c3)c2)CC1
Yield: 98.2 %

Procedure:
Following the example above and beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 3,4,5-trifluorobenzoyl chloride (30 μL, 0.229 mmol), 42.5 mg (99%) of the title compound were recovered.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([Mg]Br)[CH3:11]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:10][CH3:11]
Reactant: CC[Mg]Br
Reactant: O=Cc1ccccc1Br
Solvent: C1CCOC1
Product: CCC(O)c1ccccc1Br
Temperature: 25 °C
Yield: 102.3 %

Procedure:
A solution of 2-bromobenzaldehyde (1.85 g, 10 mmol) in THF (30 mL) at −70° C. was treated with 3 M solution of ethylmagnesium bromide (3.5 mL, 10.5 mmol). The mixture was warmed to room temperature for 6 hours and quenched with saturated solution of NH4Cl. The mixture was extracted with ethyl ether to provide the crude alcohol (yield: 2.2 g; ˜100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Br:8])[CH:3]=1.C([O-])(=O)C.[Na+].[I:14]Cl>C(O)(=O)C.C(OCC)(=O)C.ClCCl>[Br:8][C:4]1[CH:3]=[C:2]([NH2:1])[C:7]([I:14])=[CH:6][N:5]=1
Reactant: Nc1ccnc(Br)c1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)ncc1I
Temperature: 75 °C
Yield: 51.3 %

Procedure:
4-Amino-2-bromopyridine (22.8 g, 131.8 mmole) and sodium acetate (20.8 g 254 mmole) were stirred in acetic acid (82 mL) and a solution of iodine monochloride (1M in acetic acid, 134 mL, 134 mmole) was added. The mixture was stirred and heated at 75° C. for 3 hours. Most of the acetic acid was evaporated and the residue was partitioned between water (500 mL) and ethyl acetate (550 mL). The aqueous was again extracted with ethyl acetate (300 mL) The combined extracts were washed twice with 10% sodium carbonate solution (600, 300 mL), with 10% sodium thiosulfate solution (200 mL), with water and with brine, then dried and evaporated. This gave 40.3 g of a crude product mix. This was combined with the crude product from a reaction on 7.5 g of 4-amino-2-bromopyridine for purification. A large silica column (9 cm internal diameter with 28 cm bed of silica) was prepared in 5% ethyl acetate in dichloromethane. The crude material was applied in the same solvent. The column was eluted with 5% ethyl acetate in dichloromethane, with 10% ethyl acetate in dichloromethane and with 20% ethyl acetate in dichloromethane to give the desired isomer 5 (20.2 g, 38%): 1H-NMR (CDCl3, 500 MHz): δ 4.74 (br s, 2H, NH2), 6.80 (s, 1H), 8.34 (s, 1H); and subsequently with 1:1 ethyl acetate:dichloromethane to give 6 undesired isomer: 2-bromo-3-iodopyridin-4-amine 6 (19.3 g, 37%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:12][CH:11]=2)[CH:3]=1.[CH2:26](C1C=CN=C(N)C=1)[CH2:27]C>>[CH2:1]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:25])[C:10]2[CH:11]=[CH:12][C:13]([B:16]3[O:20][C:19]([CH3:21])([CH3:22])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:14][CH:15]=2)[CH:3]=1)[CH2:26][CH3:27]
Reactant: CCCc1ccnc(N)c1
Reactant: Cc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Product: CCCc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Yield: 54.1 %

Procedure:
This compound was prepared, in an analogous manner as described in Intermediate 6, starting from 4-propylpyridin-2-amine, to afford the title compound (371.5 mg, 54.1%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=O)[CH2:3][CH2:2]1.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>C(Cl)Cl>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([C:4]2[C:14]3[N:13]([CH:17]=[CH:16][N:15]=3)[CH2:2][CH2:3][CH:1]=2)=[CH:11][CH:10]=1
Reactant: c1c[nH]cn1
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Solvent: ClCCl
Product: Clc1ccc(C2=CCCn3ccnc32)cc1

Procedure:
Combine 25 g (0.14 mol) of 4-chlorophenyl cyclopropyl ketone with 50 g (0.73 mol) of imidazole, and heat to 175° C. for 18 hr. Isolation of the product by column chromatography using 200 g of silica gel and methylene chloride as solvent followed by crystallization from ether affords the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([S:27]([N:30](CC3C=CC(OC)=CC=3)[C:31]3[S:32][CH:33]=[CH:34][N:35]=3)(=[O:29])=[O:28])=[CH:24][CH:25]=2)[C:20](=[O:45])[N:19](CC2C=CC(OC)=CC=2)[CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(N)CC1C=CC=CC=1.OP(O)(O)=O>O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:17]1[C:26]2[C:21](=[CH:22][C:23]([S:27]([NH:30][C:31]3[S:32][CH:33]=[CH:34][N:35]=3)(=[O:29])=[O:28])=[CH:24][CH:25]=2)[C:20](=[O:45])[NH:19][CH:18]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)cn(Cc4ccc(OC)cc4)c(=O)c3c2)cc1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1c[nH]c(=O)c2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 110 °C
Reaction time: 4 h
Yield: 25.2 %

Procedure:
A screw capped vial was charged with 2-methoxy-4-(trifluoromethyl)phenyl boronic acid (0.094 g, 0.429 mmol), 4-chloro-N,2-bis(4-methoxybenzyl)-1-oxo-N-(thiazol-2-yl)-1,2-dihydroisoquinoline-7-sulfonamide (0.250 g, 0.429 mmol), and potassium phosphate tribasic (0.273 ml, 1.288 mmol). Dioxane (1.72 ml) and Water (0.57 ml) were added and the vial was purged with Argon and Amphos (0.030 g, 0.043 mmol) was added. The vial was capped and heated to 110° C. After 4 hours, reaction was cooled to room temperature. The reaction was diluted with water (30 mL), and was washed with ethyl acetate (20 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting material was purified via silica gel chromatography (ISCO, 40 g), eluting with 0 to 10% MeOH/DCM. The fractions were collected and the solvent was removed under reduced pressure. The resulting material was taken up in DCM (5 mL) and TFA (1 mL) was added. The reaction was stirred for 2 hours and then the solvent was removed under reduced pressure. The resulting material was taken up in DCM (30 mL) and washed with sodium bicarbonate (sat solution). The organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting solid was triturated with diethyl ether (20 mL) and filtered. The solid was dried under reduced pressure to provide 0.052 g of 4-(2-methoxy-4-(trifluoromethyl)phenyl)-1-oxo-N-(thiazol-2-yl)-1,2-dihydroisoquinoline-7-sulfonamide as an off white solid. m/z (ESI) 482.1 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH:5]([C:10]1[CH:11]=[C:12]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH:22]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:45])=[O:3])[CH:11]=[C:12]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:37][CH:36]=3)[CH:13]=2)[CH2:17]1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(C(c3ccccc3)c3ccccc3)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(C(c3ccccc3)c3ccccc3)C2)c1
Temperature: 78 °C

Procedure:
To compound 54a, 2-[5-(1-Benzhydryl-piperidin-3-yl)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid ethyl ester (37.8 mg, 0.06 mmol) in EtOH (3.1 ml) was added 2M KOH (0.31 ml, 0.62 mmol). The reaction was heated to 78° C. for 3 hour, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, salt exchange with 1N HCl (aqueous) gave the product as a white lyophilate, (30 mg, 79%). 1H NMR (300 MHz, MeOD) δ ppm 0.87-0.94 (m, 6 H) 1.37-1.49 (m, J=13.47, 6.64, 6.64, 6.41 Hz, 1 H) 1.63 (dq, J=13.80, 6.95 Hz, 1 H) 1.91-2.01 (m, 3 H) 2.03-2.63 (m, 4 H) 3.05-3.20 (m, 2 H) 3.40-3.55 (m, 1 H) 3.71 (t, J=7.35 Hz, 1 H) 5.43-5.49 (m, 1H) 7.23 (s, 1 H) 7.39-7.55 (m, 8 H) 7.63-7.78 (m, 8 H) Calcd for C37H38F3NO2 (M+H) 585.7, Found 586.3.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:10]=2[C:11]=1[CH2:12]Br)=[O:6])[CH3:3].[CH2:34]([OH:36])[CH3:35]>>[CH2:2]([O:4][C:5]([C:7]1[O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:10]=2[C:11]=1[CH2:12][O:36][CH2:34][CH3:35])=[O:6])[CH3:3]
Reactant: CCO
Reactant: CCOC(=O)c1oc2cccc(OCCCN(C(=O)OC(C)(C)C)C(C)(C)C)c2c1CBr
Agent: [Na]
Product: CCOCc1c(C(=O)OCC)oc2cccc(OCCCN(C(=O)OC(C)(C)C)C(C)(C)C)c12
Reaction time: 0.42 h

Procedure:
To ethanol (2.0 ml) was added sodium metal (15 mg) at room temperature. After 25 minutes, 3-bromomethyl-4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-benzofuran-2-carboxylic acid ethyl ester (98 mg) was added to the reaction mixture. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (10 ml) and water (20 ml). The product was extracted with ethyl acetate (10 ml) 3 times. Organic layer was combined and dried over anhydrous sodium sulfate, concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography developed by hexane-ethyl acetate to give 4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-3-ethoxymethyl-benzofuran-2-carboxylic acid ethyl ester (70 mg) as a pale yellow oil. FAB-MS: m/z 478 (MH+); 1H-NMR (CDCl3): δ 1.22 (3H, t, J=6.9 Hz), 1.37-1.47 (21H, m), 2.09 (2H, quintet, J=7.3 Hz), 3.54 (2H, t, J=7.3 Hz), 3.62 (2H, q, J=6.9 Hz), 4.12 (2H, t, J=7.3 Hz), 4.45 (2H, q, J=7.3 Hz), 5.06 (2H, s), 6.65 (1H, d, J=7.9 Hz), 7.14 (1H, d, J=7.9 Hz), 7.33 (1H, dd, J=7.9 Hz, 7.9 Hz).
Reaction SMILES: N1CCOCC1.C([O:9][C:10](=O)[C:11]([CH3:24])=[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)[CH3:13])C.O.Cl>C1(C)C=CC=CC=1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:12]([CH3:13])=[C:11]([CH3:24])[CH:10]=[O:9])=[CH:19][CH:18]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)C(C)=C(C)c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCN1
Product: CC(C=O)=C(C)c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 270 ml of morpholine in 1000 ml of absolute toluene is added dropwise at 0° C. over a period of 30-40 minutes to 740 ml of a 70% sodium dihydro-bis(2-methoxyethoxy)-aluminate solution in toluene and 1200 ml of toluene. The resulting solution is added dropwise at 0° C. over a period of 1 hour to 78.0 g of 3-(p-tert.butyl-phenyl)-2,3-dimethyl-acrylic acid ethyl ester in 340 ml of absolute toluene. The mixture is then stirred at 0° C. for 0.75 hour, poured into 3 liters of water and hydrochloric acid is added until the emulsion is eliminated. The toluene solution is separated, washed with water and sodium bicarbonate solution, dried over sodium sulphate and concentrated. By distillation there is obtained pure p-tert.butyl-α,β-dimethyl-cinnamaldehyde of boiling point 122°-128° C./0.005 Torr.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C@@H:8]2[CH2:9][C@@H:5]([CH2:6][CH2:7]2)[C@H:4]1[C:10]([O:12][CH3:13])=[O:11].C([O-])(=O)C.[Na+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:2][C@H:3]2[C@@H:8]3[CH2:9][C@@H:5]([CH2:6][CH2:7]3)[C@H:4]2[C:10]([O:12][CH3:13])=[O:11])=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H]1[C@@H]2CC[C@@H](C2)[C@@H]1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1[C@@H]2CC[C@@H](C2)[C@@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
Methyl (1R,2R,3S,4S)-3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride (1 g, 4.86 mmol) was dissolved in methanol (23 mL). Sodium acetate (0.755 g, 9.2 mmol) was added followed by 4 Å powdered molecular sieves (1 g) and 4-fluoro-benzaldehyde (0.571 g, 4.6 mmol). Sodium cyanoborohydride (0.578 g, 9.2 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (300 mL). After shaking, both layers were passed through a plug of Celite. The organic layer was further washed with saturated aqueous sodium bicarbonate solution (100 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, methyl (1R,2R,3S,4S)-3-[(4-fluorobenzyl)amino]bicyclo[2.2.1]heptane-2-carboxylate (1.172 g, 4.23 mmol, 92%), as a clear oil. LC-MS (ESI) calcd for C16H20FNO2 277.15. found 278.2 [M+H+].
Reaction SMILES: BrCCCCC.[CH2:7]([PH:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][CH2:9][CH2:10][CH3:11].P(Cl)(Cl)[Cl:20]>>[Cl:20][P:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC[PH](=O)CCCCC
Reactant: ClP(Cl)Cl
Solvent: CCCCCBr
Product: CCCCCP(Cl)CCCCC

Procedure:
Following the procedure of Example 3, 1-bromopentane (181.2 g) was used as starting material to prepare di-n-pentylphosphine oxide (22.4 g), and this compound was further reacted with phosphorus trichloride to give chloro di-n-pentylphosphine, b.p. 88° C. at a pressure of 0.3 mm of mercury. This compound (10.4 g) was added to a solution of hexamethyldisilazane (4.02 g) in dry toluene (10 cm3) under nitrogen, and the solution was heated at 100° C. for 5 hr. with distillation of chlorotrimethylsilane. The solution was cooled to 25° C. and sulphur (1.6 g) was added causing the temperature to rise to 60° C. The solution was heated to 100° C. for 4 hr. and then allowed to cool. Work up as described in Example 3 gave a crude product (10.6 g) which was also titrated in the presence of zinc and found to have a purity of 55% of theoretical (in this case based on MW 425). Further purification by chromatography on silica gel using hexane with increasing amounts of ethyl acetate (0-30% by volume) as eluent gave N-(di-n-pentylphosphinothioyl)-P,P-di-n-pentylphosphinothioic amide (2.4 g) of 95% purity, m.p. 59°-63.5° C. (MS: m/z 426, 31P NMR in CDCl3, singlet 68.3 ppm downfield of H3PO4). The compound of Formula I in which R1 =R2 =R3 =R4 =n-pentyl was tested by the procedure of Test 1. The results show that the product of this Example is a weak extractant for zinc at pH 1.7 but that it extracts zinc selectively in the presence of iron and has good solubility in ESCAID 100.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9](O)[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30](=[O:33])[NH:31][CH3:32])[C:20]([C:34]([F:37])([F:36])[F:35])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CCN(S(F)(F)[F:45])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH:9]([F:45])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30](=[O:33])[NH:31][CH3:32])[C:20]([C:34]([F:35])([F:37])[F:36])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(O)c1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(F)c1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)cc1
Yield: 19.3 %

Procedure:
A solution of diethyl[hydroxy(4-{[4-{[2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)methyl]phosphonate (Example 133, 8.00 mg, 0.014 mmol) and DAST (7 mg, 0.043 mmol) in DCM (3 mL) was stirred at 0° C. for 1 h. The was treated with sat. NaHCO3 (aq) (3 mL). The layers were separated and the aqueous layer was extracted with DCM (3×5 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated, and residue was purified by prep TLC (5% 7 N ammonia in MeOH in DCM) to give 1.5 mg of the desired product (yield: 19%). 1H NMR (CD3OD, 400 MHz): δ=1.24 (t, J=7.6 Hz, 3H), 1.32 (t, J=7.2 Hz, 3H), 2.90 (s, 3H), 4.00-4.17 (m, 4H), 5.82 (dd, J=7.2, 44.0 Hz, 1H), 7.20 (dt, J=1.2, 8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.50 (dt, J=2.0, 8.8 Hz, 1H), 7.64 (dd, J=1.2, 8.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 2H), 8.36 (s, 1H), 8.43 (d, J=7.2 Hz, 1H). MS (ES+): m/z 556.14 [MH+]. HPLC: tR=1.50 min (UPLC TOF, polar—3 min).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6]Br.[CH2:8]([NH:15][S:16]([CH2:19][C@:20]12[C:26]([CH3:28])([CH3:27])[C@H:23]([CH2:24][CH2:25]1)[CH2:22][C@H:21]2[NH2:29])(=[O:18])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C.C1(C)C=CC=CC=1>[CH2:8]([NH:15][S:16]([CH2:19][C@:20]12[C:26]([CH3:27])([CH3:28])[C@H:23]([CH2:24][CH2:25]1)[CH2:22][C@H:21]2[N:29]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)(=[O:18])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)NCc1ccccc1)[C@H](N)C2
Reactant: BrCCOCCBr
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)NCc1ccccc1)[C@H](N1CCOCC1)C2
Temperature: 25 °C

Procedure:
Bis(2-bromoethyl)ether (18.3 mL, 146 mmol) was added to a solution of (1S,2R,4R)—N-benzyl-2-amino-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethanesulfonamide (VIa) (23.5 g, 72.9 mmol) and N,N-Diisopropylethylamine (DIPEA) (55.8 mL, 320 mmol) in N,N-dimethylacetamide (DMAC) (470 mL). The solution was heated at 120° C. until the amine (1S,2R,4R)—N-benzyl-2-amino-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethanesulfonamide (VIa) was <2% by HPLC analysis. The mixture was cooled to ambient temperature and diluted with toluene (470 mL) and was extracted with water (470 mL). After layer separation, the toluene layer was washed twice with 10% aq. NaCl (230 mL each) and concentrated to give the crude product as a brown solid. The sulfonamide (1S,2R,4R)—N-benzyl-2-morpholino-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethanesulfonamide (IIa) was crystallized from a mixture of toluene (23 mL) and n-heptane (47 mL) by slowly cooling from 75° C. to 60° C., stirring at 60° C. for an hour and then cooling to ambient temperature, followed by the addition of n-heptane (70 mL) and stirring for an hour. The suspension was filtered and the powder was washed with a mixture of toluene and n-heptane (1:5, 47 mL) to give (1S,2R,4R)—N-benzyl-2-morpholino-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethanesulfonamide (IIa) as an orange to light brown powder (22.2 g; 78%; 98.9% pure as assessed by HPLC).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:17]=[CH:16][C:8]([CH:9]=[C:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[C:7]([N+:18]([O-])=O)[CH:6]=1.Cl>COCCOC.CO>[CH3:3][O:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[C:7]([CH:6]=1)[NH2:18]
Reactant: COc1ccc(C=C2CCSCC2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COc1ccc(CC2CCSCC2)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
Sodium borohydride (63.58 mg; 1.68 mmol; 0.07 eq) is suspended in DME (6.5 mL) at room temperature. Borane-methyl sulfide complex (39.61 mL; 2 M; 79.22 mmol; 3.3 eq) is added dropwise. After 30 min stirring at room temperature, a solution of 4-(4-methoxy-2-nitrobenzylidene)tetrahydro-2H-thiopyran (6.37 g; 24.01 mmol; 1 eq) in DME (100 mL) is added dropwise over 30 min and the orange solution is stirred at room temperature for 30 min then heated up to reflux for 3.5 days. The reaction mixture is quenched with MeOH (40 mL) upon which a yellow-brownish solution is obtained. The solution is stirred at room temperature for 1 h prior to evaporation of the solvent. The oily brownish residue obtained is taken up in MeOH (10 mL) and 5 N HCl (10 mL˜2 eq) is added dropwise while cooling the solution to 0° C. with an ice bath. After addition of ⅔ of the HCl, precipitation starts. The suspension is stored at 4° C. for 30 min. The precipitate is filtered off then washed twice with cold EtOAc (10 mL) to afford 2.39 g (36%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 9.61 (br s, 2H), 7.09-7.06 (m, 1H), 9.95-6.87 (m, 1H), 6.83-6.79 (m, 1H), 3.72 (s, 3H), 2.54-2.47 (m, 6H), 1.87-1.81 (m, 2H), 1.68-1.59 (m, 1H), 1.33-1.20 (m, 2H). HPLC (max plot) 95%; Rt 2.57 min. LC/MS: (ES+): 238.1; (ES−): 236.1.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nc(C)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), phenylboronic acid (1.02 g), triethylamine (1.95 mL), pyridine (1.13 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.02 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.28 g, 23%).