Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1.ClC1N=CC=CN=1>CN(C=O)C.O>[CH3:1][S:2][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: Clc1nccc(-c2ccccc2)n1
Reactant: C[S-]
Agent: Clc1ncccn1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc(-c2ccccc2)n1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of sodium methanethiolate (0.35 g) in DMF (5 ml) at 0° C. was added dropwise a solution of 2-chloro-4-phenylpyrimidine (0.86 g, prepared from 2-chloropyrimidine according to the method of D B Harden et al., J.Org.Chem., 1988, 53, 4137) in DMF (5 ml). Stirring was continued at 0° C. for 15 minutes and then the temperature was allowed to rise to room temperature. After a further 2 hours, the reaction mixture was diluted with water and then extracted with ether (×3). The combined ether extracts were washed with water, dried, filtered and evaporated to give 2-methylthio-4-phenylpyrimidine (0.76 g) as a brown solid which was used directly in the next stage.
Reaction SMILES: C(O[C@@H:6]1[O:20][C@H:19]([C@@H:21]([CH2:27][O:28][C:29](=[O:32])[CH2:30][CH3:31])[O:22][C:23](=[O:26])[CH2:24][CH3:25])[C@H:13]([O:14][C:15](=[O:18])[CH2:16][CH3:17])[C@H:7]1[O:8][C:9](=[O:12])[CH2:10][CH3:11])(=O)CC.[CH3:33][S:34][Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCCl.C(Cl)(Cl)Cl>[C:9]([O:8][C@@H:7]1[C@@H:13]([O:14][C:15](=[O:18])[CH2:16][CH3:17])[C@@H:19]([C@@H:21]([CH2:27][O:28][C:29](=[O:32])[CH2:30][CH3:31])[O:22][C:23](=[O:26])[CH2:24][CH3:25])[O:20][C@H:6]1[S:34][CH3:33])(=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)OC[C@@H](OC(=O)CC)[C@H]1O[C@@H](OC(=O)CC)[C@H](OC(=O)CC)[C@H]1OC(=O)CC
Reactant: CS[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CCC(=O)OC[C@@H](OC(=O)CC)[C@H]1O[C@@H](SC)[C@H](OC(=O)CC)[C@H]1OC(=O)CC
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 83.2 %

Procedure:
1,2,3,5,6-Penta-O-propanoyl-β-D-glucofuranose (614 mg, 1.3 mmol) was dissolved in 1,2-dichloroethane (5 mL) and cooled to 0° C. (Methylthio)trimethylsilane (567 μL, 4.0 mmol) was added dropwise followed by trimethylsilyl trifluoromethanesulfonate (72 μL, 0.4 mmol). After 20 min at room temperature, the mixture was heated at 50° C. for 3 h, cooled, diluted with CHCl3, washed with 50% aqueous NaHCO3 (30 mL), brine, dried (MgSO4) and concentrated in vacuo. Flash silica chromatography of the residue, eluting with 10% ethyl acetate in petroleum ether, gave methyl 2,3,5,6-tetra-O-propanoyl-1-thio-β-D-glucofuranoside as a colourless solid (470 mg, 81%). A sample was recrystallised from ethanol to give colourless needles, mp 62-63° C. (from EtOH), [α]D22=−50.5 (c 1.0 in CHCl3), (Found: C, 52.7; H, 7.2; S, 7.4. C19H30O9S requires C, 52.5; H, 7.0; S 7.4%); δH (CDCl3) 5.37 (1H, d, J 4.2, 3-H), 5.33 (1H, ddd, J 9.3, 5.1 and 2.5, 5-H), 5.07 (1H, d, J 2.2, 2-H), 5.00 (1H, d, J 2.2, 1-H), 4.62 (1H, dd, J 12.3 and 5.1, 2.5, 6a-H), 4.36 (1H, dd, J 9.3 and 4.2, 4-H), 4.17 (1H, dd, J 12.3 and 5.1, 6b-H), 2.39 (2H, q, J 7.6, CH2), 2.37 (2H, q, J 7.6, CH2), 2.35 (2H, q, J 7.6, CH2), 2.26 (2H, q, J 7.6, CH2), 2.23 (3H, s, SCH3) 1.16 (3H, t, J 7.6, CH3), 1.14 (3H, t, J 7.6, CH3), 1.13 (3H, t, J 7.6, CH3), 1.09 (3H, t, J 7.6, CH3); δC (CDCl3) 174.4, 173.3, 173.1, 173.1 (4×C═O), 89.6 (1-C), 81.6 (2-C), 79.1 (4-C), 74.7 (3-C), 68.4 (5-C), 63.4 (6-C), 27.7 (4×CH2), 9.4, 9.2, 9.2, 9.1 (4×CH3); m/z (FAB) 435.169691 (MH+, C19H31O9S requires 435.168880).
Reaction SMILES: [CH3:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[C:20]1[CH:21]=[C:22]([CH:25]=[O:26])[S:23][CH:24]=1>>[CH3:1][C:2]1[C:3]([C:20]2[CH:21]=[C:22]([CH:25]=[O:26])[S:23][CH:24]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Product: Cc1cc2c(cc1-c1csc(C=O)c1)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to Example 3(b), by reaction of 4.2 g (17 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid with 2.17 g (11.3 mmol) of 4-bromo-2-thiophenecarboxaldehyde, 2.75 g (78%) of the expected aldehyde are obtained, with a melting point of 144-6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46](O)=[O:47])[C:41]2=[O:49])=[CH:36][CH:35]=1>>[F:32][C:4]1[CH:3]=[C:2]([NH:1][C:46]([C:42]2[C:41](=[O:49])[N:40]([C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)[CH:45]=[CH:44][N:43]=2)=[O:47])[CH:31]=[CH:30][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[O:23])=[CH:20][CH:21]=3)[S:15][C:8]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1
Reactant: O=C(O)c1nccn(-c2ccc(F)cc2)c1=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1)c1nccn(-c2ccc(F)cc2)c1=O
Yield: 72 %

Procedure:
Prepared from (4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)(morpholino)methanone (Example 129, Step A) and 4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (3 to 5% MeOH in CH2Cl2) to afford 47 mg (72%) of the desired product. LRMS (APCI pos) m/e 666.2 (M+1). 1H-NMR (400 MHz, CDCl3/CD3OD) δ 8.47 (d, 1H), 8.06 (dd, 1H), 7.93 (d, 2H), 7.90 (d, 1H), 7.87 (s, 1H), 7.82 (d, 1H), 7.59 (m, 4H), 7.52 (d, 1H), 7.40 (t, 1H), 7.34 (m, 3H), 6.67 (d, 1H), 3.69-3.79 (m, 8H); 19F NMR (376 MHz, CDCl3/CD3OD) δ −112.7, −128.7.
Reaction SMILES: [C:1]1([OH:9])[C:2]([CH3:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH:6]=1.S(=O)(=O)(O)O.[CH3:15][C:16](=[CH2:18])[CH3:17]>O.C([O-])(O)=O.[Na+]>[C:16]([C:4]1[CH:3]=[C:2]([CH3:8])[C:1]([OH:9])=[CH:6][C:5]=1[CH3:7])([CH3:18])([CH3:17])[CH3:15]
Reactant: C=C(C)C
Reactant: Cc1ccc(C)c(O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(C)(C)C)c(C)cc1O
Yield: 49 %

Procedure:
2,5-Xylenol (90 g, 0.73 mol) was melted at 80° C., 1 mL of concentrated sulfuric acid was added, and the mixture was heated at 90° C. while isobutylene gas was introduced subsurface over 4 hours. The reaction appeared to stall at about 80% conversion. The reaction mass was diluted with water and neutralized with NaHCO3, and some starting xylenol was removed by steam-distillation. Since the steam-distillation did not completely remove the starting material, the residue was dissolved in hot hexanes, separated from the aqueous phase, and cooled in an ice-bath. The precipitated product was filtered and washed with cold hexanes to give 64 g (49%) of 4-t-Butyl-2,5-xylenol; lit. (Stevens, Ind. Eng. Chem. 1943, 655; Parc, Rev. Inst. Fr. Pet. 1960, 680) mp 70-72° C. 1H-NMR (CDCl3) δ 1.37, (s, 9H), 2.20 (s, 3H), 2.43 (s, 3H), 4.85 (s, 1H), 6.53 (s, 1H), 7.08 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][C:10]=2[F:24])[C:6]2[S:25][C:26]([CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:5]=2[C:4](=[O:33])[NH:3]1.Br[CH2:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:37].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[F:24][C:10]1[CH:11]=[C:12]([C:16]2[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[C:14]([F:15])[C:9]=1[CH2:8][N:7]1[C:6]2[S:25][C:26]([CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:5]=2[C:4](=[O:33])[N:3]([CH2:35][C:36]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[O:37])[C:2]1=[O:1]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: N#Cc1ccccc1-c1cc(F)c(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cn2c(=O)c3cc(CC(F)(F)F)sc3n(Cc3c(F)cc(-c4ccccc4C#N)cc3F)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′,5′-difluorobiphenyl-2-carbonitrile (0.65 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.34 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.082 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.5 g, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[C:10]([CH2:18][C:19](OCC)=[O:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:19](=[O:20])[CH2:18][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: COc1cccc(N)c1
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: COc1cccc(NC(=O)CC(=O)c2ccccc2)c1
Temperature: 25 °C

Procedure:
A solution of m-anisidine (10 g), ethyl benzoylacetate (19 g) and pyridine (2 drops) in xylene (20 mL) was heated to reflux for 5 hr. The mixture was cooled to r.t. and concentrated. The residual material was subjected to chromatography (silica gel; hexane/EtOAc (4:1)), affording the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[C:12]2[NH:11][CH2:10][CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C.[Cl-].[Na+].O>[C:21]([O:20][C:18](=[O:19])[CH2:17][N:7]1[C:8](=[O:13])[CH2:9][CH2:10][NH:11][C:12]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]1=2)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1CCNc2c(F)cccc2N1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)CCNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-fluoro-1,3,4,5-tetrahydrobenzo[b][1,4]diazepin-2-one from Example 1B (220 mg, 1.2 mmol) in DMF (4 ml) was added sodium hydride (60%, 48 mg, 1.2 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and was stirred for 10 min. Tert-butyl bromoacetate (190 μl, 1.2 mmol) was added and the mixture was stirred for 18 h. Brine was added and the mixture was evaporated in vacuo. The residue was partitioned between EtOAc and brine and the organic layer was reduced in vacuo. The residue was purified by flash chromatography on silica (eluant: EtOAc:pet ether 60:40); yield 240 mg, 67%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2=[N:11][CH:12]=[CH:13][C:14](Cl)=[C:9]2[NH:8][C:7]=1[CH3:16])=[O:5])[CH3:2].[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][C:27]=2[C:14]2[CH:13]=[CH:12][N:11]=[C:10]3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:16])[NH:8][C:9]=23)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ccnc12
Reactant: Cc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C)ccc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl-7-chloro-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example A3) and 2-(2-cyclopropylmethoxy-5-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c7) the title compound is obtained as pale yellow solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[C:12]1[C:17]([F:18])=[N:16][C:15]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][CH:20]=2)=[CH:14][N:13]=1>O1CCCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[F:18][C:17]1[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:13][CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][CH:20]=2)[N:16]=1
Reactant: CCCCCCCC[Mg]Br
Reactant: CCCCCCCCOc1ccc(-c2cnc(Br)c(F)n2)cc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2cnc(CCCCCCCC)c(F)n2)cc1
Reaction time: 8 h

Procedure:
7.95 mmol of freshly prepared octylmagnesium bromide in 30 ml of tetrahydrofuran are added dropwise at -10° C. to 2.00 g (5.3 mmol) of 2-bromo-3-fluoro-5-(4-octyloxyphenyl)pyrazine and 0.03 g (0.06 mmol) of [1,3-bis-(diphenylphosphino)propane]nickel(II) chloride in 30 ml of tetrahydrofuran, and the reaction mixture is stirred overnight, during which it warms to room temperature. The reaction mixture is partitioned between aqueous ammonium chloride solution and ether, the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered and freed from the solvent, and the mixture is purified by chromatography (silica gel/dichloromethane: hexane = 7:3). 1.12 g of 2-fluoro-3-octyl-6-(4-octyloxyphenyl)pyrazine are obtained. ##STR17## The compound has the following phase sequence:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]([OH:11])=O.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:16]=[C:17]([CH:21]([NH2:23])[CH3:22])[CH:18]=[CH:19][CH:20]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]([NH:23][CH:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]([F:12])([F:24])[F:25])[CH:16]=1)[CH3:22])=[O:11]
Reactant: CC(N)c1cccc(OC(F)(F)F)c1
Reactant: O=C(O)C=Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C=Cc1ccccn1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(pyridin-2-yl)acrylic acid, Preparation 16 (50 mg) in CH2Cl2 (2 mL) at room temperature were added (±)-1-(3-trifluoromethoxy phenyl)ethylamine, Preparation 15 (76 mg), EDC hydrochloride (129 mg), DMAP (41 mg), and triethylamine (0.2 mL), and the resulting solution was stirred at room temperature for 12 hours. The crude product was purified by silica gel chromatography eluting with ethyl acetate to provide the title compound as the racemate (96 mg). This racemate was separated by HPLC using AD column eluting with hexanes/ethanol (9:1) to give the title compound as an enantiomer of undetermined chirality.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[C:8]([C:14]([NH2:16])=[O:15])=[N:9][C:10]([F:13])=[CH:11][N:12]=1.N([O-])=[O:18].[Na+].C(=O)([O-])O.[Na+]>O>[F:13][C:10]1[N:9]=[C:8]([C:14]([NH2:16])=[O:15])[C:7]([OH:18])=[N:12][CH:11]=1
Reactant: NC(=O)c1nc(F)cnc1N
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1nc(F)cnc1O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 78.1 %

Procedure:
While keeping 285 ml of 97% sulfuric acid at 5-12° C. by cooling it with ice, 28.5 g of 3-amino-6-fluoro-2-pyrazinecarboxamide was added thereto to form a uniform solution. After adding 18.9 g of sodium nitrite to the solution at 5-12° C., the mixture thus obtained was stirred for 1.5 hours while cooling it with ice. While keeping the reaction mixture at a temperature not exceeding 10° C., the reaction mixture was dropwise added to 1.4 L of ice water, and the mixture thus formed was extracted first with one 850 mL portion and then two 200 mL portions of ethyl acetate. The organic layers thus obtained were united, 400 mL of water was added, then 160 mL of saturated aqueous solution of sodium hydrogen carbonate was added, pH was adjusted to 3.0, and the organic layer was separated. The organic layer thus obtained was washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was washed with a mixture of diisopropyl ether and ethyl acetate to obtain 22.4 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a solid product.
Reaction SMILES: C1(O)C=CC=CC=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=1)=[O:14].[OH-].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C=O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([C:13](=[O:14])[C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[CH:16][C:17]=1[CH3:23])[CH3:32]
Reactant: Cc1cc(C(=O)c2cccs2)cc(C)c1O
Reactant: CCOC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(C)cc(C(=O)c2cccs2)cc1C
Reaction time: 3 h

Procedure:
There was kept for 3 hours at 60° C. a solution in 150 ml of dimethylformamide of 10 g of the phenol obtained according to (B), 3 g of potassium hydroxide and 9 g of ethyl bromoacetate. The mixture was filtered, the solvent evaporated, the residue dissolved in ethyl ether, and the impurities extracted in a basic aqueous solution. After concentration of the solvent, 11.2 g of the ester were obtained which melted at 89° C.
Reaction SMILES: C(Cl)/C=C(/CCC[C@@H](CCC[C@@H](CCCC(C)C)C)C)\C.[CH3:22][C:23]1[C:32]([CH3:33])=[C:31]2[C:26]([CH2:27][CH2:28][C:29]([CH2:35][CH2:36][CH2:37][CH:38]([CH2:40][CH2:41][CH2:42][CH:43]([CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])[CH3:44])[CH3:39])([CH3:34])[O:30]2)=[C:25]([CH3:51])[C:24]=1[OH:52].[C:53](OC(=O)C)(=[O:55])[CH3:54].N1C=CC(C)=CC=1>[Zn]>[CH3:33][C:32]1[C:23]([CH3:22])=[C:24]([O:52][C:53]([CH3:54])=[O:55])[C:25]([CH3:51])=[C:26]2[CH2:27][CH2:28][C@:29]([CH2:35][CH2:36][CH2:37][C@@H:38]([CH2:40][CH2:41][CH2:42][C@@H:43]([CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])[CH3:44])[CH3:39])([CH3:34])[O:30][C:31]=12
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Reactant: CC(=O)OC(C)=O
Agent: C/C(=C\CCl)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Zn]
Solvent: Cc1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Yield: 84.7 %

Procedure:
2.283 g of TMHQ and 0.236 g of metallic zinc powder were suspended in 11.8 ml of ligroin in an atmosphere of nitrogen. A solution of 4.943 g of phytyl chloride [purity 95.7%] in 7.9 ml of ligroin was dripped into said suspension under agitation and refluxed for a period of 2 hours 15 minutes. The suspension was heated and subjected to reflux for another 3 hours to obtain a reaction mixture of dl-α-tocopherol. 11.5 ml of acetic anhydride and 0.218 g of γ-picoline were added to the reaction mixture, which was then refluxed for 5 hours, to obtain 7.118 g of dl-α-tocopheryl acetate which reflected a pale yellow coloring. The absorbance of this dl-α-tocopheryl acetate was determined to be E415 mμ40%EtOH =0.098. Estimation of the dl-α-tocopheryl acetate by high pressure liquid chromatography with the use of n-nonane as the standard substance indicated that its purity was 84.4% and the yield was 84.7%.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2]O.[C:5]1([CH3:15])[CH:10]=[CH:9][C:8](S(O)(=O)=O)=[CH:7][CH:6]=1>C1C=CC=CC=1>[CH3:15][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:5][CH2:15][CH2:2][CH2:1][OH:4]
Reactant: OCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCO

Procedure:
The synthesis of starting materials (1)-(3) is known in the art. To prepare the next intermediate, (4), 9 g (44 mmol) of (3), 20 ml of ethylene glycol, 100 ml of benzene and 3 mg of p-toluene sulfonic acid were refluxed overnight with a Dean-Stark. After evaporation of the solvent and separation on a silica gel column, 9.2 g of the cetal (4) were obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])(OCC)=O>>[C:30]1(=[O:39])[N:1]([C@H:2]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COC(=O)C[C@H](N)c1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)C[C@@H](c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O

Procedure:
Methyl (S)-3-amino-3-(3,4-dimethoxyphenyl)propionate (0.45 g, 1.63 mmol), sodium carbonate (0.17 g, 1.63 mmol) and N-carboethoxyphthalimide (0.36 g, 1.63 mmol) were allowed to react according to the procedure of Example 85. Methyl (S)-3-phthalimido-3-(3,4-dimethoxyphenyl)propionate was obtained as a white powder, 0.51 g (85%); 1H NMR (DMSO-6, 250 MHz) δ7.87 (br s, 4H, Ar), 6.80-7.10 (m, 3H, Ar), 5.65 (dd, 1H, J1 =7 Hz, J2 =9 Hz), 3.73 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.55 (s 3H, OCH3), 3.30-3.67 (m, 2H); 13C NMR (DMSO-d6) δ170.8, 167.7, 148.6, 148.4, 134.7, 131.1, 131.0, 123.2, 119.3, 111.7, 111.0, 55.5, 51.6, 49.9, 35.6. Anal. Calcd for C20H19 NO6. Theoretical C, 65.03; H, 5.18; N, 3.79. Found C, 64.94; H, 5.29; N, 3.86. HPLC 97%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH2:39][C:40](O)=[O:41])[CH:36]=[CH:37][CH:38]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[Cl:32][C:33]1[CH:34]=[C:35]([CH2:39][C:40]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]4[N:14]=[C:15]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]6[CH2:28][CH2:29][CH2:30][CH2:31]6)=[CH:20][CH:19]=5)[N:16]=[C:12]4[CH:11]=[CH:10][CH:9]=3)[CH:3]=2)=[O:41])[CH:36]=[CH:37][CH:38]=1
Reactant: Nc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1cccc(Cl)c1)Nc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reaction time: 8 h

Procedure:
[5-(3-Amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (50 mg, 0.121 mmol), 3-chlorophenylacetic acid (25 mg, 0.145 mmol) and di-isopropylethylamine (25 μL, 0.145 mmol) were dissolved in dimethylacetamide (1 ml). HBTU (55 mg, 0.145 mmol) was subsequently added and the mixture was stirred overnight. The product was purified by preparatory HPLC. RT: 2.9 min, MI: 567, Method: 2.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[CH3:15].[OH-].[K+].[CH2:18](I)[CH3:19]>CS(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])([CH3:14])[CH2:7][C:8](=[O:12])[N:9]2[CH2:18][CH3:19])=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc2c(cc1Br)NC(=O)CC2(C)C
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A solution of 8.5 g of 7-bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinolin-2-one (31.7 mmol), prepared according to WO 03/075924, in 15 mL dry DMSO was added to a prestirred solution of crushed potassium hydroxide (3.56 g, 63.4 mmol) in 15 mL of dry DMSO, followed by addition of 7.68 mL (95.2 mmol) of ethyl iodide. The reaction was stirred overnight before quenching with 100 mL of water and extracted with dichloromethane (3×150 mL), the extracts were dried with sodium sulfate, filtered, stripped and purified via flash chromatography (5% EtOAc/hexanes) to afford 8.3 g of product (88%) as a white solid. MS (electrospray): mass calculated for C14H18BrNO, 295.06; m/z found 296, [M+H]+.