Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13](NC1C=CC(C(O)=O)=CN=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[CH2:34]([O:36][C:37](=[O:47])[CH:38]=[CH:39][C:40]1[CH:41]=[N:42][C:43]([NH2:46])=[CH:44][CH:45]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:47])[CH:38]=[CH:39][C:40]1[CH:41]=[N:42][C:43]([NH:46][C:13](=[O:14])[CH2:12][CH2:11][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:33])[N:8]2[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[CH:44][CH:45]=1)[CH3:35]
Reactant: CCOC(=O)C=Cc1ccc(N)nc1
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Product: CCOC(=O)C=Cc1ccc(NC(=O)CCC2c3c(F)cccc3C(=O)N2Cc2ccc(F)cc2)nc1

Procedure:
The product of Example 11, Part D (137 mg, 0.41 mmol) and 3-(6-amino-pyridin-3-yl)-acrylic acid ethyl ester (80 mg, 0.41 mmol) were converted to the title compound in a manner analogous to the method described in Example 27 (90.8 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 8.3 (s, 1H), 8.18 (d, J=8.7 Hz, 1H), 8.03 (s, 1H); 7.89-7.86 (d, J=8.6 Hz, 1H); 7.71 (d, J=7 Hz, 1H); 7.62 (d, J=16 Hz, 1H), 7.49-7.44 (m, 1H); 7.34 (m, 2H); 7.23 (t, J=8.75 Hz, 1H); 7.04 (t, J=8.8 Hz, 2H); 6.44 (d, J=16 Hz, 1H); 5.28 (d, J=15 Hz, 1H), 4.70 (m, 1H), 4.29-4.23 (m, 3H); 2.57-2.50 (m, 2H); 2.04-1.93 (m, 2H); 1.36 (t, J=7.4 Hz, 3H) MS: m/z (MH+) 506.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.Cl.[O:33]=[C:34]1[C:42]2[C:37](=[CH:38][C:39]([N:43]([CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)[S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:41]=2)[C:36](=[O:56])[N:35]1[CH2:57][C:58](O)=[O:59]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:58](=[O:59])[CH2:57][N:35]1[C:36](=[O:56])[C:37]2[C:42](=[CH:41][CH:40]=[C:39]([N:43]([CH2:48][CH2:49][N:50]3[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]3)[S:44]([CH3:47])(=[O:46])=[O:45])[CH:38]=2)[C:34]1=[O:33]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CS(=O)(=O)N(CCN1CCCCC1)c1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)N(CCN1CCCCC1)c1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Reaction time: 96 h
Yield: 52.1 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (188 mg, 0.449 mmol), DMAP (110 mg, 0.897 mmol) and EDC (129 mg, 0.673 mmol) in DCM (10 ml), 2-(1,3-dioxo-5-(N-(2-(piperidin-1-yl)ethyl)methylsulfonamido)isoindolin-2-yl)acetic acid hydrochloride (200 mg, 0.449 mmol) was added portion wise over 5 hours, and the resulting mixture was stirred at room and for 96 hours. The solvent was removed and the crude was purified by silica gel chromatography (EtOAc/DCM 2/1 then DCM/MeOH 100/3). The resulting white solid was triturated with EtOH and recovered by filtration affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(1,3-dioxo-5-(N-(2-(piperidin-1-yl)ethyl)methylsulfonamido)isoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (190 mg, 0.234 mmol, 52.2% yield, LC-MS purity (BPI): 98.3%, MS/ESI+ 811.21 [MH]+, [αD]=+28.12, c=0.653 DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 7.97 (d, 1H), 7.95 (d, 1H), 7.89 (dd, 1H), 7.19 (d, 1H), 7.09 (d, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.02 (dd, 1H), 4.43 (s, 2H), 3.91-4.04 (m, 2H), 3.88 (t, 2H), 3.38 (dd, 1H), 3.23 (dd, 1H), 3.15 (s, 3H), 2.35 (t, 2H), 2.17-2.31 (m, 4H), 1.03-1.53 (m, 7H), 0.49-0.68 (m, 2H), 0.28-0.46 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]([OH:10])=O.O=S(Cl)[Cl:13]>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]([Cl:13])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCOCCCBr
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)CCOCCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(3-bromopropoxy)propionic acid (15.2 g, 72.2 mmol) in CCl4 (250 mL) was added SOCl2 (5.5 mL, 76.0 mmol) and DMF (20 drops) and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure to give the title intermediate, which was used without further purification.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:22])=[O:21]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Temperature: 0 °C

Procedure:
To 215.2 g (2.72 mole) of pyridine in 1250 ml of dichloromethane is added 238 g (1.44 mole) of ethyl 4-aminobenzoate. After cooling to 0° C., a solution of 177.6 g (1.55 mole) of methanesulfonyl chloride in 250 ml of dichloromethane is added with stirring. Upon completion of the addition, the ice bath is removed and the reaction is stirred for one hour at room temperature.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9](F)[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4](Cl)=[O:5].[Br:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[F:14][C:7]1[C:8]([F:13])=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=1[C:4]([C:18]1[S:17][C:16]([Br:15])=[CH:20][CH:19]=1)=[O:5]
Reactant: Brc1cccs1
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(c1ccc(Br)s1)c1c(F)c(F)cc(F)c1F
Reaction time: 2.5 h
Yield: 33.3 %

Procedure:
To a mixture of perfluorobenzoyl chloride (2.51 g, 10.9 mmol) and 2-bromothiophene (1.86 g, 11.4 mmol) in carbon disulfide (80 mL), aluminum chloride (2.90 g, 21.8 mmol) was added in portions over 10 min with vigorous mechanical stirring. The reaction mixture turned red and was stirred for 2.5 h before being quenched with water (80 mL). The organics were then separated, the aqueous layer extracted with carbon disulfide (3×50 mL), and the combined organics washed with water (3×100 mL) and dried over MgSO4. After filtration, the organics were concentrated in vacuo and the chromatographed on a silica gel column (hexane:ether=9:1) to yield 1.23 g (32%) green crystals. mp 51-54° C.; 1H NMR (DMSO): δ 7.78 (d, 2H, 3J=3.6 Hz), 7.54 (d, 2H, 3J=4.4 Hz); 19F NMR (DMSO): δ −142.1 (m, 2H), −151.6 (m, 1H), −160.6 (m, 2H) Anal. Calcd for C11H2BrF5OS: C 37.00, H 0.56. Found: C 37.37, H 0.83; MS (EI): m/z (%) 355.8 (92) [M+].
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[S:60]1[CH2:64][C@@H:63]([C:65](OCC#N)=[O:66])[N:62]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH2:61]1>C(#N)C>[S:60]1[CH2:64][C@@H:63]([C:65]([O:40][C@H:39]2[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36][C@@H:35]2[CH2:34][O:33][P:30]([O:29][C@H:28]2[CH2:27][C@H:26]([N:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]3=[O:59])[O:25][C@@H:24]2[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:66])[N:62]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH2:61]1
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.6 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (148 mg, 0.233 mmol) and (R)-3-tert-butyl 4-(cyanomethyl) thiazolidine-3,4-dicarboxylate (Compound tk28) (254 mg, 0.933 mmol) in acetonitrile (0.7 mL) was added to buffer A (30 mL), and the mixture was stirred at room temperature for 1.5 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (4R)-4-((2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl) 3-tert-butyl thiazolidine-3,4-dicarboxylate (Compound tk29) (64.7 mg, 33%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27].[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[CH3:38]>O>[C:37]([N:40]1[CH2:45][CH2:44][N:43]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]3[C:8](=[O:27])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=4)[CH2:14][CH2:13][CH2:12][O:11][C:10]=3[N:15]=2)[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Reactant: CC(=O)N1CCNCC1
Solvent: O
Product: CC(=O)N1CCN(c2cc(-c3ccccc3C)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Temperature: 150 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
A mixture of 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 17; 100 mg) and 1-acetylpiperazine (73.0 mg) was stirred at 150° C. for 5 hours. To the resulting residue, water was added, and then the mixture was subjected to extraction with ethyl acetate. The resulting extract was dried on anhydrous sodium sulfate. The solvent was removed by distillation to obtain a residue, and then the residue was purified on silica gel column chromatography (ethyl acetate: methanol=10:1) to obtain 9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (44.6 mg, 38%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.CO[CH:13](OC)[CH2:14]Br>O1CCOCC1.O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]2[CH:13]=[CH:14][N:1]=[C:2]2[CH:7]=1
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: COC(CBr)OC
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(Cl)cc2nccn12

Procedure:
75 g (427 mmol) of 4-amino-6-chloro-2-(methylthio)pyrimidine are dissolved in 3000 ml of dioxane and 750 ml of water. 101.05 g (597.81 mmol) of bromoacetaldehyde dimethyl acetal are added, and the mixture is heated under reflux for 24 h. After the reaction is complete, the dioxane is removed in vacuo and the aqueous suspension is suspended in THF, filtered with suction and washed with some THF. Drying of the solid at 40° C. under high vacuum results in 56.5 g (66% of theory) of the product.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:4]=2[N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)CCC>[F:12][C:10]1[CH:9]=[CH:8][C:5]2[N:6]([CH3:7])[C:2]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:3][C:4]=2[CH:11]=1
Reactant: Cn1c(Cl)nc2cc(F)ccc21
Reactant: C1CNCCN1
Solvent: CCCCO
Product: Cn1c(N2CCNCC2)nc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.7 g 2-chloro-5-fluoro-1-methyl-1H-benzimidazole and 1.3 g piperazine are suspended in 10 ml n-butanol and stirred for 48 hours at ambient temperature. The reaction mixture is evaporated to dryness and the product is purified by chromatography (aluminium oxide, methylene chloride/methanol 10/1). 0.73 g (V-8) are obtained as a solid. 1H NMR (400 MHz, DMSO): 6.9 (1H, t); 3.6 (3H, s).
Reaction SMILES: [CH:1]([S:4][CH:5]([C:17]([OH:19])=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:35][C:36]1[CH:49]=[CH:48][CH:47]=[CH:46][C:37]=1[C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:39]>C(Cl)Cl>[CH:1]([S:4][CH:5]([C:17]([NH:35][C:36]1[CH:49]=[CH:48][CH:47]=[CH:46][C:37]=1[C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:39])=[O:19])[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])([CH3:2])[CH3:3]
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: CC(C)SC(NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)SC(NC(=O)OCc1ccccc1)C(=O)Nc1ccccc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
α-(isopropylthio)-N-(benyloxycarbonyl)glycine 22B was dissolved in methylene chloride (200 mL) under nitrogen atmosphere at 0° C. in a three necked flask carrying an additional funnel. To the stirred solution was added N-methylmorpholine (2.11 mL, 19.3 mmol) followed by isobutylchloroformate (2.48 mL, 19.2 mmol). This was stirred for 15 minutes at 0° C. and then heated to reflux. To the refluxing reaction mixture was added a solution of 2-aminobenzophenone 23 (3.59 g, 18.19 mmol) in dry methylene chloride (26 mL) over 20 minutes. The reaction mixture was stirred for 20 more minutes after the addition and then left stirring overnight at room temperature. The reaction mixture was washed with 10% citric acid, saturated sodium bicarbonate solution and brine, then dried over magnesium sulphate. Solvent evaporated at reduced pressure to give 9.30 g of the crude product 24. This was used without further purification.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:3][CH:2]=1.[CH2:29](C1C=CC(N=C=O)=CC=1)C>>[CH2:28]([C:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[C:22]([C:24]([F:26])([F:27])[F:25])[N:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:5][CH:6]=1)[CH3:29]
Reactant: Cc1ccc(NC(=O)Nc2ccc(Oc3cc(C(F)(F)F)ncn3)cc2)cc1
Reactant: CCc1ccc(N=C=O)cc1
Product: CCc1ccc(NC(=O)Nc2ccc(Oc3cc(C(F)(F)F)ncn3)cc2)cc1
Reaction time: 2.5 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(6-trifluoromethyl-pyrimidin-4-yloxy)-phenylamine (Example 114) and 4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 2.5 h. The title compound is obtained as a white solid: ES-MS: 403.0 [M+H]+; single peak at tR=9.72 min (System 2).
Reaction SMILES: [F:1][C:2]([F:31])([CH3:30])[CH2:3][N:4]([CH2:27][CH2:28][OH:29])[C:5]([C:7]1[C:11](O)=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:8]=[C:7]3[C:11]=2[O:29][CH2:28][CH2:27][N:4]([CH2:3][C:2]([F:1])([F:31])[CH3:30])[C:5]3=[O:6])=[CH:14][CH:15]=1
Reactant: CC(F)(F)CN(CCO)C(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1O
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(F)(F)CN1CCOc2c(nn(-c3ccccc3Cl)c2-c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(2-chloro-phenyl)-5-(4-chloro-phenyl)4-hydroxy-1H-pyrazole-3-carboxylic acid (2,2-difluoro-propyl)-(2-hydroxy-ethyl)-amide I-3d (10 g, 21 mmol), triphenyl phosphine (8.4 g, 31.5 mmol) in toluene (210 ml) was added 1,1′-(azodicarbonyl)dipiperidine (8.0 g, 31.5 mmol). After 18 hours, 20% ethyl acetate:hexanes (210 ml) was added, the mixture was stirred at ambient temperature for 1 hour and filtered. The filtrate was concentrated in vacuo and the resulting oil was chromatographed on silica gel (20–70% ethyl acetate:hexanes) to afford the title compound (2A-1) as a solid, 7.8 g. 1H NMR in CDCl3 (ppm) δ 7.53–7.50 (m, 1H), 7.38–7.33 (m, 3H), 7.24–7.21 (m, 2H), 7.16–7.13 (m, 2H), 4.45 (br s, 2H), 4.02 (t, 2H), 3.90 (br s, 2H), 1.69 (t, 3H); ms (LCMS) m/z=452.2 (M+1). Combustion analysis calculated for: C: 55.77%; H: 3.79%; N: 9.29%. Found: C: 55.69%; H: 3.52%; N: 9.13%.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[K]>CN(C=O)C.O>[CH:2]1([N:12]2[C:8](=[O:18])[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11]2=[O:13])[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: BrC1C=CCCC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1C=CCCC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 73717.9 %

Procedure:
To a solution of 3-bromo-cyclohexene (500 g, 3.12 mmol) in DMF (2000 mL) was added potassium phtalimide (580 g, 3.12 mmol), and the reaction mixture was stirred at room temperature for 30 h. The reaction mixture was diluted with water (1000 mL), extracted with ethyl acetate (3 times), and the combined organic layers were concentrated to give 2-cyclohex-2-enyl-isoindole-1,3-dione (520 g, 2.30 mol) as a gray solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]2[C:14](=[S:15])[NH:13][N:12]=[CH:11]2)[CH:7]=[CH:6][C:5]=1[O:16][CH3:17].[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]2[CH:11]=[N:12][N:13]=[C:14]2[S:15][CH3:19])[CH:7]=[CH:6][C:5]=1[O:16][CH3:17]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(-n2cn[nH]c2=S)ccc1OC
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(-n2cnnc2SC)ccc1OC
Yield: 72 %

Procedure:
Treat a stirred mixture of 2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acid methyl ester (3.80 g, 14.38 mmol), potassium carbonate (2.19 g, 15.8 mmol) and anhydrous acetone (60 mL) with methyl iodide (1.07 mL, 17.25 mmol) added dropwise via syringe. Reflux the stirred mixture for 2.5 hours, cool, filter and wash the filter cake twice with acetone. Combine the acetone phases, concentrate in vacuo, dissolve the residue in ethyl acetate and wash with NaHCO3 solution. Extract the combined aqueous phases three times with ethyl acetate. Combine the ethyl acetate phases, wash with saturated NaHCO3 and brine, dry (MgSO4), filter and concentrate in vacuo to afford an oil. Purify the oil by flash chromatography (silica gel, 5.5×15.2 cm) eluting with ethyl acetate and then with 5% methanol in dichloromethane after elution of the starting material. Concentrate the appropriate fractions to afford 2.89 g of 2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid methyl ester as a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([C:11]1([CH3:26])[CH2:16][CH2:15][C:14]2[C:17]([CH3:25])=[C:18]([O:23][CH3:24])[C:19]([CH3:22])=[C:20]([CH3:21])[C:13]=2[O:12]1)C(OCC)=O)C.[OH-].[K+]>C(O)CO.O>[CH3:24][O:23][C:18]1[C:19]([CH3:22])=[C:20]([CH3:21])[C:13]2[O:12][C:11]([CH3:26])([CH2:5][C:4]([OH:27])=[O:3])[CH2:16][CH2:15][C:14]=2[C:17]=1[CH3:25]
Reactant: CCOC(=O)C(C(=O)OCC)C1(C)CCc2c(C)c(OC)c(C)c(C)c2O1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)O)O2
Yield: 75.9 %

Procedure:
A mixture of 1.29 g (3.41 mmoles) of rac.-3,4-dihydro-2,5,7,8-tetramethyl-6-methoxy-2H-1-benzopyran-2-ylpropanedioic acid diethyl ester, 1.68 g of potassium hydroxide, and 75 ml of 9:1 parts by volume ethylene glycol-water mixture was stirred and refluxed for 6 hours. The resulting mixture was poured on ice and extracted with ether (the ether extract was discarded). The aqueous solution was acidified with 3N HCl and the preciptated acid was extracted 3 times with ether. The combined ether extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by preparative thick layer chromatography gave 0.72 g (75.9%) of rac.-3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetic acid, as a colorless solid, mp 96°-98° C. Demethylation using the procedure of example 14 gives rac.-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetic acid which can be converted to alpha-tocopherol as described in Helv. Chim. Acta. 59, 290 (1976).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9]C(C)(O)C)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[CH:3]=1
Reactant: CC(C)(O)C#Cc1cccc(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C#Cc1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 36 h
Yield: 66.2 %

Procedure:
Add dry toluene to a degassed mixture of 4-(3-chlorophenyl)-2-methylbut-3-yn-2-ol (21.1 g, 0.109 mol), potassium carbonate (45 g, 0.326 mol) and 18-crown-6 (6.89 g, 0.026 mol). Stir at 90° C. for 36 h. Cool the reaction mixture to room temperature, filter and wash with toluene. Concentrate and purify the residue by silica gel chromatography, eluting with 18:1 o 13:1 hexanes:ethyl acetate, to give the title compound (9.85 g, 66%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][CH2:19][CH2:18][CH2:17]3)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:24])[N:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[NH2:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][CH2:19][CH2:18][CH2:17]3)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:24])[N:3]=1
Reactant: COC(=O)c1c(C)nc(N)c(CO)c1-c1ccc2c(c1)CCCO2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1c(C)nc(N)c(C=O)c1-c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
A mixture of crude methyl 6-amino-4-(chroman-6-yl)-5-(hydroxymethyl)-2-methylnicotinate in dichloromethane (DCM) (264 mL) was treated with PCC (5.78 g, 26.8 mmol) and the mixture was stirred overnight at ambient temperature. The mixture was filtered over Celite™ and the filtrate was concentrated and purified on silica gel to afford methyl 6-amino-4-(chroman-6-yl)-5-formyl-2-methylnicotinate as a yellow solid (4.5 g, 13.79 mmol, 66.8% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.66 (s, 1 H), 7.00 (dd, J=2.0, 8.3 Hz, 1 H), 6.95 (s, 1 H), 6.84 (d, J=8.4 Hz, 1 H), 4.26-4.23 (m, 2 H), 3.54 (s, 3 H), 2.81 (t, J=6.4 Hz, 2 H), 2.48 (s, 3 H), 2.08-2.02 (m, 2 H); LC/MS (m/z) ES+=327.25 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH2:22][CH2:23][CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([CH2:22][CH2:23][CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CCCC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Agent: [Pd]
Product: CCCC(Cc1ccc(O)cc1)C(=O)OCC
Yield: 107.1 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)-2-propylpropionate (4.00 g) and palladium on carbon (5%, 0.40 g) and the reaction mixture was treated to afford the desired compound (3.10 g) as a syrup.