Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)N.C(O[CH:17](OCC)[CH2:18][CH2:19][CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])C.C(OCC)(=O)C>C(O)(=O)C>[O:31]=[C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29](=[O:30])[N:21]1[CH2:20][CH2:19][C:18]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([NH2:13])=[O:12])[CH:8]=2)[NH:2][CH:17]=1
Reactant: NNc1ccc(CC(N)=O)cc1
Reactant: CCOC(CCCN1C(=O)c2ccccc2C1=O)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
A mixture of the crude 2-(4-hydrazinophenyl)acetamide hydrochloride (16.19 g) (contains 0.05 mol) and 4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butanal diethyl acetal (14.5 g) was heated under reflux in 25% aqueous acetic acid (1 l) for 30 min. The cooled mixture was poured into ethyl acetate (750 ml) the organic phase was separated and the aqueous phase was washed with ethyl acetate (250 ml). The combined organic extracts were washed with water (500 ml), dried (Na2SO4) and evaporated under reduced pressure. Water (500 ml) was added to the oily residue which solidified on stirring. The solid was collected by filtration, washed with water and dried. Crystallisation from ethyl acetate-methanol gave the title compound as pale yellow granules (11.9 g) m.p. 191°-3° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([OH:11])[C:8]([Br:12])=[CH:7][C:6]=1[Br:13])(=[O:3])[CH3:2].C(O[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=C.F[C:24](F)(F)[C:25](O)=[O:26].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:25]([O:11][C:9]1[CH:10]=[C:5]([O:4][CH:1]([O:3][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH3:2])[C:6]([Br:13])=[CH:7][C:8]=1[Br:12])(=[O:26])[CH3:24]
Reactant: CC(=O)Oc1cc(O)c(Br)cc1Br
Reactant: O=C(O)C(F)(F)F
Reactant: C=COC1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(OC(C)OC2CCCCC2)c(Br)cc1Br
Temperature: 25 °C
Reaction time: 21 h
Yield: 669.8 %

Procedure:
Under nitrogen, 2,4-dibromo-5-hydroxyphenyl acetate (4.00 grams, 12.9 millimoles, 1.0 equivalent) and cyclohexyl vinyl ether (2.74 milliliters, 19.3 millimoles, 1.5 equivalents) was dissolved in toluene (50 milliliters). Trifluoroacetic acid (0.10 milliliters, 1.29 millimoles, 0.10 equivalent) was added, and the mixture stirred at room temperature overnight (18-24 hours). The reaction was quenched by adding triethylamine (0.53 milliliters, 3.87 millimoles, 0.3 equivalent), and the volatiles were removed on the rotary evaporator. The resulting oil was taken up in diethyl ether (30 milliliters) and filtered through a plug of basic alumina. The product was rinsed through with additional ether (500 milliliters). The solvent was removed on the rotary evaporator and the resulting oil was pumped on for over 24 hours. The product was obtained as a racemate in the form of a slightly yellow oil (3.77 grams, 8.64 millimoles, 67%). 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.00 (s, 1H), 5.48 (q, J=5.4 Hz, 1H), 3.69 (tt, J=9.1, 3.9 Hz, 1H), 2.34 (s, 3H), 1.94-1.63 (m, 4H), 1.55-1.48 (m, 1H), 1.52 (d, J=5.3 Hz, 3H), 1.44-1.02 (m, 5H); 13C NMR (101 MHz, THF-d8) δ 168.19, 154.65, 149.40, 136.68, 114.35, 111.79, 108.79, 100.94, 75.66, 34.45, 33.33, 26.69, 24.97, 24.85, 20.94, 20.55; FTIR (film) 647, 703, 725, 840, 891, 979, 1018, 1059, 1170, 1190, 1248, 1279, 1368, 1393, 1466, 1584, 1779, 2856, 2932 cm−1; UV/Vis 223, 232 (overlapping), 290 nm; ESI/MS/MS of m/z=459: 459 [M79Br/81Br+Na]+, 341, 281, 207, 151, 109 83 [C6H11]+; HRMS (ESI+): calc. for C16H20Br2NaO4+[M+Na]+456.9621, found 456.9628.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2].[F:17][C:18]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2.[F-].[Cs+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:19]2[C:18]([F:17])=[C:26]3[C:22]([CH:23]=[CH:24][NH:25]3)=[CH:21][CH:20]=2)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc3cc[nH]c3c2F)OC1(C)C
Reactant: COC(=O)c1nc(Cl)cc(NC(C)=O)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2ccc3cc[nH]c3c2F)cc(NC(C)=O)c1Cl
Yield: 95.3 %

Procedure:
Methyl 4-acetamido-3,6-dichloropicolinate (400 mg, 1.520 mmol), 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (437 mg, 1.673 mmol), cesium fluoride (462 mg, 3.04 mmol), and (PPh3)2PdCl2 (107 mg, 0.152 mmol) were charged as solids into a microwave reaction vessel and dioxane (4 mL) and water (1 mL) were added. The reaction vessel sealed and irradiated in a Biotage Initiator microwave at 110° C. for 2 h, with external IR-sensor temperature monitoring from the side. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was filtered and concentrated. The intermediate product was purified by flash chromatography (ISCO 40 g silica 10-75% EtOAc: Hex 16 CV). Fractions containing product were combined and concentrated to give 524 mg of a white solid intermediate methyl 4-acetamido-3-chloro-6-(7-fluoro-1H-indol-6-yl)picolinate (0.524 g, 1.448 mmol) which was subsequently diluted with methanol (10.0 mL). Then acetyl chloride (0.725 mL, 10.20 mmol) was added. The reaction mixture was allowed to stir at room temperature for 18 h. The reaction was concentrated to dryness. The resulting residue was dissolved in ethyl acetate and poured into saturated NaHCO3 solution. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (3×15 mL). The organic extracts were combined, washed with saturated NaCl solution, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified using a Teledyne ISCO purification system with a gradient eluent system of ethyl acetate and hexanes to yield the title compound as a white solid (365 mg, 79%).
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][C@H:35]([C:38](C)(C)[O:39][SiH2]C(C)(C)C)[CH2:36][CH3:37])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1>[F:55][C:2]([F:1])([F:54])[C:3]1[CH:4]=[C:5]([CH:47]=[C:48]([C:50]([F:51])([F:52])[F:53])[CH:49]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][C@H:35]([CH2:38][OH:39])[CH2:36][CH3:37])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2N[C@@H](CC)C(C)(C)O[SiH2]C(C)(C)C)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2N[C@@H](CC)CO)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
Ethyl 4-[2-((3,5-bis-trifluoromethyl-benzyl)-{2-[(S)-1-(tert-butyl-dimethyl-silanyloxymethyl)-propylamino]-5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yloxy]-butyrate (183 mg) is dissolved in tetrahydrofuran (3 mL) and thereto is added 1M-tetrabutylammonium fluoride/tetrahydrofuran solution (1 ml) and the mixture is stirred at room temperature for 20 minutes. The reaction solution is concentrated under reduced pressure and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-((S)-1-hydroxymethyl-propylamino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (93 mg). MS (m/z): 697 [M+H]+
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=N[CH:5]=[CH:6][N:7]=1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:25].[C:33](=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:3]([CH:8]3[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]3)=[CH:33][CH:5]=[CH:6][N:7]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C1CCC(c2nccnc2Cl)CC1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
4-(3-Chloropyrazin-2-yl)cyclohexanone (0.10 g, 0.48 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.34 g, 1.42 mmol), and cesium carbonate (0.46 mL, 1.42 mmol) were mixed in NMP (1.5 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 140° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was washed with 1 M aqueous sodium hydroxide, washed with sat. sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give 4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)cyclohexanone. MS (ESI, pos. ion) m/z: 413.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:23][CH2:22][N:21]([C@@:24]4([CH3:42])[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C:30]([NH:33]C(=O)OC(C)(C)C)([CH3:32])[CH3:31])[CH2:25]4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[N:13]=2)=[CH:4][N:3]=1.Cl.O1CCOCC1.C1(C)C=CC=CC=1>CO>[NH2:33][C:30]([CH3:31])([CH3:32])[C:29]([N:26]1[CH2:27][CH2:28][C@@:24]([N:21]2[C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]4[CH3:20])[N:13]=[C:8]([C:5]4[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=4)[C:9]=3[CH2:23][CH2:22]2)([CH3:42])[CH2:25]1)=[O:41]
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCN(C(=O)C(C)(C)NC(=O)OC(C)(C)C)C1)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: Cc1ccccc1
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCN(C(=O)C(C)(C)N)C1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 971.8 %

Procedure:
To a solution of tert-butyl {1-[(3S)-3-{4-(2-aminopyrimidin-5-yl)-2[(3S)-3-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-3-methylpyrrolidin-1-yl]-2-methyl-1-oxopropan-2-yl}carbamate (778 mg, 0.1 mmol) in MeOH (6.5 mL) was added 4 N HCl in dioxane (6.7 mL, 26.8 mmol) dropwise at 0° C. and the reaction was stirred at room temperature for 2 h. Toluene was added and the mixture was concentrated to give a residue that was purified by SFC/ZymorSpher HAP column (150×21.2 mm) eluting with 15-35% CO2 in MeOH over 6 min at 120 bar and with a flow of 100 mL/min to give 468 mg of the title compound as a white solid. The solid was treated with hydroxide resin in MeOH for 15 min or until pH˜8 was reached. The resin was removed by filtration washing with MeOH and 7 N ammonia in MeOH several times. The filtrate was concentrated under reduced pressure, dried under high vacuum and lyophilized to give the title compound (387.8 mg, 60%) as a white solid. 1H NMR (400 MHz, DMSO-d6, 80° C.) δ 8.73 (s, 2 H), 6.60 (br s, 2 H), 4.63 (d, J=6.6 Hz, 1 H), 4.36-4.16 (m, 2 H), 4.00 (d, J=11.6 Hz, 1 H), 3.94-3.85 (m, 1 H), 3.75-3.37 (m, 7 H), 3.22-3.05 (m, 3 H), 2.44-2.29 (m, 1 H), 2.08-1.95 (m, 1 H), 1.69 (br s, 2 H), 1.32 (s, 3 H), 1.28 (s, 6 H), 1.22 (d, J=6.72 Hz, 3 H). m/z (APCI+) for C24H35N9O2 482.6 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:39])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:35])([CH3:34])[CH:32]=[CH2:33])[NH:17][CH:16]2[C:36](O)=[O:37])[CH:12]=[CH:13][CH:14]=1.[CH3:40][C:41]1([CH3:49])[O:45][C@@H:44]([CH2:46][CH2:47][NH2:48])[CH2:43][O:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:40][C:41]1([CH3:49])[O:45][C@@H:44]([CH2:46][CH2:47][NH:48][C:36]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:39])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:35])([CH3:34])[CH:32]=[CH2:33])[NH:17]2)=[O:37])[CH2:43][O:42]1
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: C=CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(C)(C)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 80 %

Procedure:
In a manner similar to the method described in Example 42c, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 80c (1.0 g, 1.69 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.73 g, 5.0 mmol), HATU (1.15 g, 3 mmol) and iPr2NEt (1.46 mL, 8.4 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide as a white solid (0.82 g, 80%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][NH:8][C:9]1[CH:10]=[N:11][N:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:13]=1>ClC(Cl)C>[CH3:7][N:8]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:13]=1)[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CNc1cnn(-c2cccnc2)c1
Solvent: CC(Cl)Cl
Product: CC(C)C(=O)N(C)c1cnn(-c2cccnc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.3 %

Procedure:
A solution of isobutyryl chloride (0.138 g, 1.3 mmol) in dichloroethane (1 mL) was pipetted at a dropwise rate into an ice-cold suspension of methyl-(1-pyridin-3-yl-1H-pyrazol-4-yl)-amine (0.15 g, 0.86 mmol) in dichloroethane (5 mL), stirred for 10 minutes and then treated at a dropwise rate with a solution of 4-N,N-dimethylaminopyridine (0.11 g, 0.9 mmol) in dichloroethane (1.5 mL). The cooling bath was removed after 30 minutes, stirred under nitrogen at room temperature for 14 hours, diluted with dichloroethane (40 mL), washed with water (30 mL), brine (10 mL), dried over MgSO4 and purified by reversed phase column chromatography to give a yellowish gum (0.114 g, 54%) 1H NMR (300 MHz, CDCl3) δ 9.01-8.93 (m, 1H), 8.67 (s, 0.4H), 8.61 (d, J=4.2 Hz, 0.6H), 8.54 (d, 0.4H), 8.08-8.02 (m, 1H), 7.96 (s, 0.6H), 7.80 (s, 0.4H), 7.70 (s, 0.6H), 7.47-7.37 (m, 1H), 3.49 (s, 1.2H), 3.26 (s, 2.8H), 3.06-2.98 (m, 0.4H), 2.86-2.70 (m, 0.6H), 1.25 (d, J=6.1 Hz, 2.4H), 1.09 (d, J=6.6 Hz, 3.6H). ESIMS m/z 245 ([M+1]).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH3:5][C:6]1[C:7](O)=[C:8]([CH3:14])[C:9]([CH3:13])=[C:10]([CH:12]=1)O.[CH3:16][CH:17]([CH2:19][CH2:20][CH2:21][CH:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH2:29][CH2:30][CH2:31][C:32]([OH:36])([CH:34]=[CH2:35])[CH3:33])[CH3:28])[CH3:23])[CH3:18].C(OC(=O)C)(=O)C>>[CH3:13][C:9]1[C:8]([CH3:14])=[C:7]([O:3][C:1]([CH3:2])=[O:4])[C:6]([CH3:5])=[C:12]2[CH2:35][CH2:34][C@:32]([CH2:31][CH2:30][CH2:29][C@@H:27]([CH2:26][CH2:25][CH2:24][C@@H:22]([CH2:21][CH2:20][CH2:19][CH:17]([CH3:16])[CH3:18])[CH3:23])[CH3:28])([CH3:33])[O:36][C:10]=12
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2

Procedure:
The condensation of trimethylhydroquinone monoacetate (TMHQ-MA) with isophytol is described in DE-OS 2 160 103 (=U.S. Pat. No. 3,789,086). With the use of Fe (II) Cl2 and hydrochloric acid and simultaneous removal of the water of reaction, only small quantities of α-tocopherol acetate are obtained and it is necessary to acetylate subsequently with amine catalysis and addition of hyperstoichiometric quantities of acetic anhydride. The yields are unsatisfactory, the two-step procedure is expensive and the necessity of reacting with hyperstoichiometric quantities of acetic anhydride to obtain vitamin E acetate entails a high consumption of chemicals. The working-up of the catalyst phase obtained after the reaction is not dealt with.
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:7][NH:6][CH2:5][CH:4]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[CH2:3]1.C(N(CC)CC)C.[NH2:21][C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](Cl)[N:23]=1>CS(C)=O>[NH2:21][C:22]1[N:23]=[C:24]([N:6]2[CH2:7][C:2]([F:1])([F:13])[CH2:3][CH:4]([C:8]([N:10]([CH3:11])[CH3:12])=[O:9])[CH2:5]2)[CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29]
Reactant: CN(C)C(=O)C1CNCC(F)(F)C1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C1CN(c2ccc([N+](=O)[O-])c(N)n2)CC(F)(F)C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
To a solution of 5,5-difluoro-N,N-dimethylpiperidine-3-carboxamide (700 mg, 3.05 mmol) in dimethylsulfoxide (30 mL) were added triethylamine (619.2 mg, 6.11 mmol) and 2-amino-6-chloro-3-nitropyridine (531.1 mg, 3.059 mmol). The reaction mixture was heated to 100° C. After 16 h, the mixture was cooled to room temperature and was partitioned between ethyl acetate and water (2×). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was triturated with pentane to afford 1-(6-amino-5-nitropyridin-2-yl)-5,5-difluoro-N,N-dimethylpiperidine-3-carboxamide (0.9 g) as a yellow solid. MS (ES+APCI) (M+H) 330.2; LCMS retention time: 3.066 min (Method U1).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:28])[N:12]([CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[O:20][CH2:21][C:22]([OH:24])=[O:23])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.CCOC(C)=O>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:28])[N:12]([CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[O:20][CH2:21][C:22]([O:24][CH3:35])=[O:23])[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)COc1cccc(CCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(CCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Reaction time: 5 h

Procedure:
To a solution of (3-{3-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]propyl}phenoxy)acetic acid (100 mg) in DMF (2 mL) was added K2CO3 (46 mg) and iodomethane (41 mg) at ambient temperature. The reaction mixture was stirred for 5 hours at the same temperature. The resulting mixture was diluted with EtOAc and washed successively with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=80:20-40:60) to give methyl (3-{3-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]propyl}phenoxy)acetate-.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[C:30]1[C:31]([C:46](OCC)=O)=[CH:32][C:33]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:34][CH:35]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)=[CH:32][C:31]=1[CH2:46][C:13]1([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N#CC1CCCCC1
Reactant: CCOC(=O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(CC3(C#N)CCCCC3)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere, to a solution of diisopropylamine (0.13 mL) in THF (7 mL) was added a solution (1.6 M, 0.58 mL) of butyllithium in hexane at 0° C., and the mixture was stirred at 0° C. for 10 min. The reaction mixture was cooled to −78° C., and cyclohexanecarbonitrile (0.12 mL) was added. The mixture was stirred at −78° C. for 1 hr, and a solution of ethyl 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-carboxylate (201 mg) in THF (3 mL) was added. The mixture was stirred at −78° C. for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (168 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:21]([N:22]=O)=[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[N:5]2[N:4]=1.O.C(O)(=O)C>C(O)C.[Zn]>[CH3:1][O:2][C:3]1[C:21]([NH2:22])=[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[N:5]2[N:4]=1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(N=O)c(OC)nn12
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(C)cc(C)c1-c1cccc2c(N)c(OC)nn12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-Methoxy-7-(2-methoxy-4,6-dimethylphenyl)-3-nitrosopyrazolo[1,5-a]pyridine (200 mg) was suspended in ethanol (10 mL), and then water (5 mL), acetic acid (0.5 mL) and zinc powder (200 mg) were added and the mixture was heated and stirred at 60° C. for 1 hour. The reaction mixture was filtered, water was added to the filtrate, extraction was performed with ethyl acetate and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then the solvent was concentrated under reduced pressure to obtain 2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridine-3-amine as a crude product. This was dissolved in tetrahydrofuran (5 mL) without purification, and after adding cyclopropanecarboxyaldehyde (0.166 mL) and 3 M aqueous sulfuric acid (0.739 mL), sodium borohydride (56 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (240 mg) was obtained from the n-hexane:ethyl acetate (30:1) fraction as a yellow oil.