Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12](OS(C)(=O)=O)[C:11]2=[O:20])[CH:7]=[CH:8][CH:9]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[N:23]([CH:12]1[CH2:13][CH2:14][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:22])([F:21])[F:1])[CH:5]=2)[C:11]1=[O:20])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC1CCN(c2cccc(OC(F)(F)F)c2)C1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC1CCN(c2cccc(OC(F)(F)F)c2)C1=O
Reaction time: 16 h
Yield: 104.6 %

Procedure:
A stirred solution of crude 1-(3-trifluoromethoxyphenyl)-3-methanesulfonyloxy-2-pyrrolidinone (4.00 g) in DMF (15 ml) was treated with sodium azide (0.76 g) and the mixture stirred for 16 hours. The mixture was poured into water and extracted with diethyl ether (x2). The combined ether extracts were washed with water (x3) and brine, then dried (MgSO4). Evaporation of the solvent under reduced pressure gave the crude sub-title compound (3.50 g), which was used without further purification.
Reaction SMILES: C1C[N:4]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1CCN2C(=NCCC2)CC1.[S:45]([C:49]1[CH:50]=[C:51]([O:63][CH2:64][C:65]([OH:67])=O)[C:52]2[C:57]([CH:58]=1)=[CH:56][C:55]([S:59]([OH:62])(=[O:61])=[O:60])=[CH:54][CH:53]=2)([OH:48])(=[O:47])=[O:46]>CN(C=O)C>[S:45]([C:49]1[CH:50]=[C:51]([O:63][CH2:64][C:65]([NH2:4])=[O:67])[C:52]2[C:57]([CH:58]=1)=[CH:56][C:55]([S:59]([OH:62])(=[O:61])=[O:60])=[CH:54][CH:53]=2)([OH:48])(=[O:47])=[O:46]
Reactant: O=C(O)COc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)ccc12
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: NC(=O)COc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)ccc12
Reaction time: 8 h
Yield: 33 %

Procedure:
The dendrimer (DAB-Am-32; 185 mg; Mw: 3,514) dissolved in DMF (10 mL) then added PyBop (1.84 g; 2.1 eq; Mw: 520.4), followed by a solution of DBU (1 mL) and 3,6-disulfo-1-naphthoxyacetic acid (1.22 g; 2 eq; Mw: 362.3) in DMF (10 mL). The reaction mixture was left to stir overnight at R.T under N2. The solvent was removed under reduced pressure. Then purified through a sephadex (LH20) column followed by an Ion-exchange (IR120; Na+) and freeze-dried to yield SPL7320 as a white powder (402 mg, 48%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([C:10]([C:12]1[C:17](F)=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:11])=[CH:6][N:7]([CH3:9])C)[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:28]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1CN>CC(N(C)C)=O>[CH2:1]([O:3][C:4]([C:5]1[C:10](=[O:11])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][N:13]=2)[N:7]([CH2:9][C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=1)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ncccc1F
Reactant: NCc1ccccc1-c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cn(Cc2ccccc2-c2ccccc2)c2cccnc2c1=O
Temperature: 70 °C
Reaction time: 14 h
Yield: 39 %

Procedure:
To a stirred solution of 3-dimethylamino-2-(3-fluoro-pyridine-2-carbonyl)acrylic acid ethyl ester (4) (18 mg, 0.067 mmol) in dimethylacetamide (2 mL) was added K3PO4 (28 mg, 0.14 mmol) followed by C-biphenyl-2-yl-methylamine (5) (11 mg, 0.06 mmol) at room temperature. The mixture was stirred at 70° C. for 14 h. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using normal silica gel column chromatography (3% methanol:dichloromethane) to get 1-biphenyl-2-ylmethyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (6) (9 mg, 35%) as a sticky solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][S:26]([CH3:25])(=[O:28])=[O:27])=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Cc2ccc(N)nc2)c(F)c1-c1cccc(Cl)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(Cc2ccc(NS(C)(=O)=O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32 %

Procedure:
To a solution of 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylamine (P-252) synthesized above (70 mg, 0.18 mmol) in pyridine (2 ml) was added methanesulfonyl chloride (23 mg, 0.20 mmol) at 0 C under nitrogen, and stirred at room temperature for 20 h. The reaction mixture was diluted with water, neutralized with 6N HCl, extracted with ethyl acetate, washed with water and brine, and dried over Na2SO4. After it was concentrated in vacuo, the residue was purified by a chromatography on silica gel to yield N-[5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-methanesulfonamide (P-258) (25 mg, 32%). 1H NMR (400 MHz, CDCl3) 8.15 (s, 1H), 7.58 (dd, J=8.8, 2.1 Hz, 1H), 7.38 (s, 1H), 7.34 (t, J=6.6 Hz, 3H), 7.24-7.31 (m, 2H), 7.11 (t, J=8.5 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 3.89 (s, 2H), 3.77 (s, 3H), 3.09 (s, 3H) ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2].S(=O)(=O)(O)O.[Br:17]N1C(=O)CCC1=O>>[Br:17][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([CH:1]=[O:2])[CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: O=Cc1cc(Br)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
Into a round bottom flask were combined 3-formylbenzoic acid (10.0 g, 66.6 mmol) and sulfuric acid (653 g, 6.66 mol). N-Bromosuccinimide (14.23 g, 79.9 mmol) was added portion wise over a 10 minute period and the reaction was stirred at room temperature for 3 h upon which the mixture was poured over ice. The white precipitate that formed was filtered, washed with cold water (5×100 mL), and recrystallized from water-ethanol to afford the title compound as a white solid (12.98 g, 76.6%). LC-MS: 227.0 [M−1]−; 1H NMR (400 MHz, DMSO-d6): 10.05 (s, 1H), 8.40 (t, 1H, J=1.5 Hz), 8.3 (d, 2H, J=1.5 Hz).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43]([C:46](O)=[O:47])([CH3:45])[CH3:44])=[CH:33][CH:32]=2)=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=1)(=O)C.[OH:53][CH2:54][CH2:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43]([C:46]([N:59]4[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][OH:53])[CH2:57][CH2:58]4)=[O:47])([CH3:45])[CH3:44])=[CH:35][CH:36]=3)=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: OCCN1CCNCC1
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCCC(=O)NC(C)(C)C(=O)N2CCN(CCO)CC2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{4-[1-carboxy-1-(methyl)ethyl-carbamoyl]butyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][C:10]([OH:12])=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:13][O:14][C:15]([C:17]1[C:22]([NH2:23])=[N:21][CH:20]=[CH:19][N:18]=1)=[O:16].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[CH3:13][O:14][C:15]([C:17]1[C:22]([NH:23][C:10](=[O:12])[CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=2)=[N:21][CH:20]=[CH:19][N:18]=1)=[O:16]
Reactant: O=C(O)Cc1ncc(Cl)cc1Cl
Reactant: COC(=O)c1nccnc1N
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1nccnc1NC(=O)Cc1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.5 %

Procedure:
To a solution of (3,5-dichloro-pyrid-2-yl)-acetic acid (Example 5.1) (5.7 g) and 3-amino-pyrazine-2-carboxylic acid methyl ester (4.65 g) in dichloromethane (120 ml) were added successively triethylamine (8.5 ml) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (7.5 g). The reaction mixture was stirred at ambient temperature for 24 hours. The organic phase was washed successively with water, aqueous sodium hydrogen carbonate (1M), and brine. The organic phase was dried over magnesium sulfate and concentrated to give 3-[2-(3,5-dichloro-pyrid-2-yl)-acetylamino]-pyrazine-2-carboxylic acid methyl ester (6.37 g). 1H-NMR (400 MHz, CDCl3): 4.04 (s, 3H), 4.35 (s, 2H), 7.77 (s, 1H), 8.39 (s, 1H), 8.49 (s, 1H), 8.56 (s, 1H), 11.02 (s, 1H) ppm.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH2:13][NH2:14])[CH2:4][C:5]([NH2:12])([C:9]([OH:11])=[O:10])[CH:6]([F:8])[F:7].O.[ClH:16]>C1COCC1>[OH2:10].[ClH:16].[F:7][CH:6]([F:8])[C@@:5]([C:9]([OH:11])=[O:10])([CH2:4][CH2:3][CH2:13][NH2:14])[NH2:12]
Reactant: NCCCC(N)(C(=O)O)C(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NCCC[C@](N)(C(=O)O)C(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a dry 100 ml three necked RB flask equipped with a stirrer, gas inlet and outlet arrangement methyl-2,5-di[1-(3,4-chlorophenyl)methylidene amino]pentanoate (2.0 g) and sodium hydride (0.21 g) in dry THF (20 ml) were added. The resulting suspension was stirred at 50° C. under a nitrogen atmosphere for 2 hrs. The reaction mixture was then cooled to 5° C. and the nitrogen inlet was replaced with chlorodifluoromethane gas tube. The gas was passed for about 45 mts. The reaction was stirred at RT and allowed to stand overnight. The reaction mixture was worked up by quenching with water and the pH was adjusted to 2 with aqueous HCl. The reaction mixture was extracted with MDC twice. The water layer was concentrated and taken up in methanol and chilled. The crystallized inorganic material was removed. The filtrate was concentrated and the residue taken up in 6N HCl and hydrolyzed. The resulting aqueous layer was evaporated. The crude product was dissolved in ethanol, chilled again to remove any inorganic material and further purified by water-acetone to give a product with a melting point (mp) 223-225° C. with spectral data such as NMR matching with material obtained in Example 8.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=O>O1CCCC1.C(OCC)C>[Cl:19][CH2:20][C:21]1[N:2]2[N:1]=[CH:5][CH:4]=[C:3]2[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1-c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: ClCc1nc2ccccc2c2ccnn12
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
2.1. 8.6 g of 2-(1H-pyrazol-3-yl)aniline are dissolved in 800 ml of tetrahydrofuran. 75.3 g of potassium carbonate are added thereto, the mixture is cooled to 5° C. and then a solution of 6.7 ml of chloroacetyl chloride in 40 ml of diethyl ether is added dropwise thereto within 10 min. The mixture is stirred at 5° C. for 30 min. and then a solution of 0.67 ml of chloroacetyl chloride in 5 ml of diethyl ether is again added dropwise thereto. The mixture is stirred for a further 15 min. and then the insoluble constituent is filtered off, The filtrate is evaporated in a vacuum. The residue is partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The aqueous phase is extracted several times with dichloromethane. The organic extracts are dried and evaporated in a vacuum. The residue is taken up in 560 ml of a 0.41N solution of hydrogen chloride in dioxan and stirred at 90° C. for 1 h. The solution is evaporated in a vacuum and the residue is partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The dichloromethane extract is evaporated in a vacuum. 11.4 g of 5-(chloromethyl)-pyrazolo[1,5-c]quinazoline are obtained. The m.p. is 135°-136° C. after recrystallization from diisopropyl ether.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]1[CH2:10][S:9][C:8]2([CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)[S:7]1)(=[O:3])[CH3:2].Cl[CH2:22]C1CSC2(CCCC(CC(OCC)=O)C2)S1.C([O-])(=S)C.[K+]>CN(C=O)C>[C:1]([S:4][CH2:5][CH:6]1[CH2:10][S:9][C:8]2([CH2:14][CH2:13][CH2:22][CH:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)[S:7]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC1CCC2(C1)SCC(CSC(C)=O)S2
Reactant: CCOC(=O)CC1CCCC2(C1)SCC(CCl)S2
Agent: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCCC2(C1)SCC(CSC(C)=O)S2

Procedure:
The titled compound was synthesized according to the procedure used for the synthesis of the thioacetate of Example F using the chloride of Example H derived from the less polar pair of racemates (0.62 g, 0.002 mole) and potassium thioacetate (917 mg) in DMF (15 ml). The crude product was chromatographed on silica gel using 10% ethyl acetate/hexane to give 0.57 g of the titled product (Product A.)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[C:6]([F:13])[CH:5]=1)([O-:3])=[O:2].Cl.[CH3:15][NH:16][O:17][CH3:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>N1C=CC=CC=1>[CH3:18][O:17][N:16]([CH3:15])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[F:13]
Reactant: CNOC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 60 °C
Reaction time: 15 h
Yield: 85.2 %

Procedure:
4-Nitro-2-fluorobenzoic acid (5.03 g) was dissolved in pyridine (60.0 ml), and N,O-dimethylhydroxylamine hydrochloride (7.95 g), HOBt (5.50 g), and EDC (7.79 g) were added thereto. The obtained mixture was stirred at 60° C. for 15 hours. After the reaction mixture was allowed to cool, the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the obtained residue, and extraction and washing were carried out. The organic layer was sequentially washed with a 1N hydrochloric acid aqueous solution, saturated sodium-bicarbonate aqueous solution, and saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized with a mixed solvent of tert-butylmethylether and n-heptane to obtain Compound 14a (5.28 g, 85%) as an opalescent solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:25]([CH3:31])([C:26](OCC)=[O:27])[C:24](=[O:32])[NH:23][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:9]=2)[N:7]=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[NH2:1][C:2]1[C:3]2[C:25]([CH3:31])([C:26]([NH:36][CH:33]3[CH2:35][CH2:34]3)=[O:27])[C:24](=[O:32])[NH:23][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:20])([F:22])[F:21])[N:9]=2)[N:7]=1
Reactant: NC1CC1
Reactant: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)F)c4ncccc34)nc(N)c21
Product: CC1(C(=O)NC2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)F)c4ncccc34)nc(N)c21

Procedure:
To the intermediate from Step A above (165 mg, 0.367 mmol) was added cyclopropylamine (3.31 mL, 47.7 mmol) and the resultant mixture heated to 50° C. for 16 hours. The reaction mixture was concentrated in vacuo and the residue purified by silica gel column chromatography using a DCM/MeOH (with 0.5% NH4OH) gradient. Chiral separation using SFC on a Chiralcel OJ-H column provided both enantiomers of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 11.23 (1H, s), 9.02 (1H, dd, J=8.08, 1.55 Hz), 8.62 (1H, dd, J=4.50, 1.57 Hz), 7.64 (1H, d, J=4.05 Hz), 7.37 (1H, dd, J=8.08, 4.49 Hz), 6.76 (2H, s), 4.81 (2H, t, J=6.60 Hz), 3.06-2.94 (2H, m), 2.67-2.60 (1H, m), 1.55 (3H, s), 0.62-0.53 (2H, m), 0.50-0.41 (2H, m). m/z=461.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:21])=O>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:5][Cl:21])=[CH:7][CH:8]=[CH:9][C:10]=1[S:11][C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: COc1c(CO)cccc1Sc1ccccc1C
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1c(CCl)cccc1Sc1ccccc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-methoxy-3-(o-tolylthio)benzyl alcohol (8.5 g), thionyl chloride (4.8 ml) and pyridine (3 drops) in benzene (80 ml) was stirred at room temperature and then at 80° C. for 10 minutes. The reaction mixture was treated in a similar manner to that of Example 21-(6) to give oily o-tolyl 2-methoxy-3-chloromethylphenyl thioether (8.3 g).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].CC1C(O)=C(C)C2CC[C@](CCC[C@@H](CCC[C@@H](CCCC(C)C)C)C)(C)OC=2C=1C.CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)/C=C/C1C(C)(C)CCCC=1C>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Agent: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The food additive is prepared by combining a sterol and/or stanol ester of a fatty acid made by the process described herein and an edible solubilizing agent, an effective amount of a suitable antioxidant and an effective amount of a suitable dispersant. The solubilizing agent can be vegetable oil such as, for example, sunflower oil, palm kernel oil, coconut oil, rape seed oil, tallow, corn oil, canola oil, linseed oil, palm oil, olive oil, sesame oil, safflower oil, and the like, monoglycerides, diglycerides, triglycercides, tocopherols, and the like, and mixtures thereof. The antioxidant can be ascorbic acid (Vitamin C), tocopherols such as α-tocopherol (vitamin E), β-carotene, an extract of the bark of the maritime pine, Pinus maritima and combinations thereof. The extract of the bark of the maritime pine, also known as PYCNOGENOL™, contains procyanidines consisting of catechin and epicatechin units linked by C—C bonds to form dimers, trimers and other oligomers up to a chain length of 6-7 molecules and phenolic acids and its glucose derivatives. PYCNOGENOL™ is produced according to U.S. Pat. No. 4,698,360, which is incorporated herein for reference. The extract used according to the invention may be prepared essentially by extracting maritime pine bark in comminuted form with boiling water, saturating the filtered extract with sodium chloride or, alternatively, adding ammonium sulfate to 20% w/v, separating the precipitate formed, repeatedly extracting the supernatant with {fraction (1/10)} volume of ethyl acetate, drying the collected ethyl acetate extracts, concentrating the dried extract, pouring it into 3 volumes of chloroform with stirring and collecting the precipitate which may be purified by repeating the dissolution in ethyl acetate and precipitation with chloroform. Mixtures of the above antioxidants can also be used.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[CH:18]([O:17][CH:11]([CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][CH2:2][O:1][C:30]([NH:29][C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:28][CH:27]=2)=[O:31])[CH:5]=1)[C:12]([OH:14])=[O:13])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OC(C)C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: CC(C)OC(Cc1cccc(CCOC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)O

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=O)[CH2:6][CH2:5]2.[N:13](OCCC(C)C)=O.Cl.O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH2:7][CH:6]([NH2:13])[CH2:5]2
Reactant: O=C1CCc2cc(F)c(F)cc21
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CO
Solvent: O
Product: NC1Cc2cc(F)c(F)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (4.60 g, 27.4 mmol) in MeOH (90 mL) at 40° C. was added isoamyl nitrite (4.17 g, 35.6 mmol) followed by concentrated HCl (2.7 mL). Upon heating for 45 min the solution was cooled to room temperature and water was added. Precipitated solid was collected by filtration and rinsed thoroughly with water affording 3.97 g of a light orange solid. The solid was dissolved in HOAc (100 mL), conc HCl (8 mL) was added, followed by 10% Pd/C (1.07 g). The mixture was hydrogenated under 50 psi H2 for 24 hr using a Parr hydrogenation apparatus, and filtered through a bed of Celite (CHCl3 wash). The filtrate was concentrated in vacuo and the residue was dissolved in water. The aqueous solution was basified with solid K2CO3, extracted with CHCl3 (3×), combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (MeOH/CH2Cl2) affording the title compound as a brown oil. 1H NMR (400 MHz, CDCl3) δ 6.95 (t, 2H, J=8.9 Hz), 3.83 (m, 1H), 3.10 (dd, 2H, J=15.8 & 6.8 Hz), 2.60 (dd, 2H, J=15.8 & 5.0 Hz); (M+H) 170, 0.68 min (LC/MS method A).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:10]=1Br.[Li]CCCC.CN(CCN(C)C)C.[CH:37]1[CH:42]=[C:41]([CH:43]=[O:44])[N:40]=[CH:39][CH:38]=1>CCOCC>[N:40]1[CH:39]=[CH:38][CH:37]=[CH:42][C:41]=1[CH:43]([C:10]1[C:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[OH:44]
Reactant: O=Cc1ccccn1
Reactant: Brc1c(COC2CCCCO2)cccc1COC1CCCCO1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1ccccn1)c1c(COC2CCCCO2)cccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
To a solution of 2,6-di(tetrahydro-2H-2-pyranyloxymethyl)-phenyl bromide (15.5 g, 39 mmol) in ether at -30° C. was added n-BuLi (2.5M, 16.4 ml, 41 mmol) and the mixture was allowed to warm to room temperature and stirred for 1.5 hours. The mixture was cooled to 0° C., and TMEDA (4.56 g, 37 mmol) was added, and the resulting mixture was cooled to -50° C. After stirring for 20 minutes, 2-pyridylcarboxaldehyde (6.31 g , 58 mmol) was added. The above mixture was warmed to room temperature over a period of 2 hours, quenched with saturated sodium bicarbonate, and diluted with ethyl acetate with stirring. The organic layer was washed with brine and concentrated in vacuo to afford 11.7 g (73%) of 1-(2-pyridyl)-1-[2,6-di(tetrahydro-2H-2-pyranyloxymethyl)phenyl]-methanol as an oil.