Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@@H:12]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:16][C@@H:15]2[O:29][C:30]([CH3:33])([CH3:32])[O:31][C@@H:14]2[C@H:13]1[O:34]C(=O)C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(OCC)(=O)C>CO>[CH2:1]([O:8][NH:9][C:10]([C@@H:12]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:16][C@@H:15]2[O:29][C:30]([CH3:32])([CH3:33])[O:31][C@H:14]2[C@H:13]1[OH:34])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N2C[C@@H]3OC(C)(C)O[C@@H]3[C@@H](OC(C)=O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2C[C@@H]3OC(C)(C)O[C@H]3[C@@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
The above compound (4) (1.85 g) was dissolved in methanol (25 mL) and 28% NaOMe (668 mg) was added, and then the mixture was stirred at room temperature for 2 hours. Furthermore, 28% NaOMe (334 mg) was added and, after stirring at room temperature for 3 hours, the reaction solution was mixed with ethyl acetate (150 mL) and then washed with 0.5N hydrochloric acid and saturated saline. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure, and then the resulting residue was purified by silica gel medium pressure column chromatography (ethyl acetate:cyclohexane=2:3) to obtain the titled compound (1.36 g) as a syrup.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:5]=[CH:4]1.Cl[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[CH3:18][Si:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][O:14][CH2:13][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:5]=[CH:4]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
To a stirred suspension of sodium hydride (572 mg, 23.8 mmol, 94%) in dry DMF (50 mL) at 0° C. was added methyl 1H-imidazole-4-carboxylate (3.0 g, 23.8 mmol) in DMF (90 mL) and was allowed to warm up to room temperature over 30 min. The reaction mixture was cooled to 0° C. and was treated dropwise with (2-(chloromethoxy)ethyl)trimethylsilane (Aldrich, 4.77 g, 28.6 mmol). The cold bath was removed and the mixture was stirred for 16 h. The reaction mixture was quenched by the addition of ice-flakes and then by water, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude product. The crude material was purified by flash chromatography (gradient from 2 to 5% MeOH/CH2Cl2) to provide the title compound (4.46 g, 73%). 1H NMR (CDCl3) δ 7.72 (s, 1H), 7.61 (s, 1H), 5.29 (s, 2H), 3.90 (s, 3H), 3.49 (t, J=8.0 Hz, 2H), 0.90 (t, J=8.0 Hz, 2H), 0.01 (s, 9H); MS(ESI+) m/z 257.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([S:22][CH3:23])=[N:14][C:15]=2[NH:17]C[C@@H](O)C)[NH:10][N:9]=1>N.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([S:22][CH3:23])=[N:14][C:15]=2[NH2:17])[NH:10][N:9]=1
Reactant: CSc1nc(NC[C@H](C)O)c2c(-c3ccccc3Cl)n[nH]c2n1
Agent: N
Solvent: CO
Product: CSc1nc(N)c2c(-c3ccccc3Cl)n[nH]c2n1
Temperature: 80 °C

Procedure:
200 mg of 4-chloro-3-(2-chloro-phenyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine (from step 4 of Example 1) was dissolved in 5 ml of 7N ammonia in methanol, and the solution was stirred at 80° C. over night in a sealed tube. The resulting reaction mixture was concentrated under vacuum and then extracted in 60 ml ethylacetate. The solution was washed first with water and next with brine, dried and after removing the solvent in vacuo afforded 190 mg (90%)) of 3-(2-chloro-phenyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-4ylamine as a light tan solid, MS: 292 (M+H). The crude 3-(2-chloro-phenyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-4ylamine was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([CH:12]3[CH:16]([O:17]C(=O)C)[CH2:15][CH:14]([CH2:21][O:22][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[O:13]3)[C:6]=2[N:7]=1>CO>[CH:26]([O:25][C:23](=[O:24])[O:22][CH2:21][CH:14]1[CH2:15][CH:16]([OH:17])[CH:12]([N:8]2[C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[CH:4][C:5]=3[S:10][C:9]2=[O:11])[O:13]1)([CH3:28])[CH3:27]
Reactant: CC(=O)OC1CC(COC(=O)OC(C)C)OC1n1c(=O)sc2cnc(N)nc21
Solvent: CO
Product: CC(C)OC(=O)OCC1CC(O)C(n2c(=O)sc3cnc(N)nc32)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.5 %

Procedure:
Compound 4 (0.50 g, 1.21 mmol) was dissolved in MeOH (5.0 mL) and TEA (0.51 mL, 3.63 mmol) was added. The solution was stirred at rt for 48 hr and warmed to 35° C. from 48 to 72 hr. The reaction was removed from heat, concentrated in vacuo, then submitted to flash chromatography (0-100% EtOAc-DCM) yielding 0.298 g (66%) of 5 as a white powder: 1H NMR (400 MHz, DMSO-d6): 8.33 (1H, s), 6.85 (2H, bs), 5.85 (1H, d, J=2.3 Hz), 5.52 (1H, d, J=4.1 Hz), 4.79-4.83 (1H, m), 4.71 (1H, septet, J=6.2 Hz), 4.35-4.41 (1H, m), 4.23 (1H, dd, J1=3.8 Hz, J2=11.9 Hz), 4.06 (1H, dd, J1=8.0 Hz, J2=11.9 Hz), 2.40-2.47 (1H, m), 1.86-1.91 (1H, m), 1.20 (3H, d, J=1.4 Hz), 1.19 (3H, d, J=1.4 Hz); [M+H]+ at m/z 370.9. Analysis calc'd for C14H18N4O6S: C, 45.40; H, 4.90; N, 15.13; S, 8.66. Found: C, 45.07; H, 4.84; N, 14.70; S, 8.51.
Reaction SMILES: [OH-].[K+:2].[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:13][C@@H:14]([CH3:18])[CH2:15][O:16][CH3:17])[CH:12]=1)[C:7]([OH:9])=[O:8].O.C1(C)C=CC=CC=1>C(O)CC>[K+:2].[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:13][C@@H:14]([CH3:18])[CH2:15][O:16][CH3:17])[CH:12]=1)[C:7]([O-:9])=[O:8]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC[C@H](C)Oc1cc(O)cc(C(=O)[O-])c1
Temperature: 67 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
KOH liquor (1.04 eq. of 50.4 wt %) was added to a stirred, nitrogen sparged solution of 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid (1 eq.) in undried 1-propanol (4.87 vol.). At the end of the addition, water (0.33 vol.) and toluene (3.43 vol.) were separately added to the resulting slurry. The jacket temperature was raised to 67° C. before being subjected to the following cooling profile: 67° C. to 64° C. over 3 h, 64 to 57° C. over 3 h, 57 to 45° C. over 3 h, and 45 to 20° C. over 3 h. 6 h after the end of this ramp, the jacket temperature was lowered to 0° C. over 3 h, the jacket was foil wrapped and desupersaturation was allowed to complete overnight (>6 h). The slurry was isolated by filtration through an 11 micron filter paper. The cake was sequentially washed twice with an equal weight of an ice-cold solution of toluene (41.79 wt %) in 1-propanol. The cake was dried in a 40° C. house vacuum oven to give 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid potassium salt as tri-hydrate in a typical yield of 93% of theoretical yield.
Reaction SMILES: [CH:1](=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]>CCCCCCC>[CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCCCCCC=O
Solvent: CCCCCCC
Product: C=CCCCCCCCCCO
Temperature: 70 °C

Procedure:
Undec-10-enal (84 g, 0.5 mol.), heptane (84 g, 100 wt. %, technical grade), and (ethylenediamine)[1,2-bis(diphenylphosphino)ethane]ruthenium[bis((adamantane-1-carboxylate)] (45.9 mg, 0.05 mmol, 0.01 mol.%) were loaded altogether in a 300 ml autoclave equipped with a mechanical stirring device. Sealed autoclave was then purged under stirring with nitrogen (3 times 5 bars) and hydrogen (3 times 5 bars) before being pressurized to 10 bars hydrogen. It was then heated to 70° C. and hydrogen pressure was maintained to 10 bars during all the reaction to afford desired product with 90% selectivity. After complete reaction conversion (checked by both hydrogen consumption and GC), autoclave was cooled down to 25° C. It was then depressurized and purged with nitrogen (3 times 5 bars) and reaction mixture was then transferred to a round-bottomed flask and solvent was removed under vacuum. After initial flash distillation and further fractional distillation, undec-10-en-1-ol was obtained in 85% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.P(Br)(Br)[Br:22]>C1COCC1>[Br:22][CH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[C:4]([CH3:10])[CH:5]=1
Reactant: BrP(Br)Br
Reactant: Cc1cc(CO)cc(C)c1-c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: Cc1cc(CBr)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a solution of (2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yl)-methanol (2.22 g, 7.9 mmol) in THF (30 ml) is added PBr3 (3.22 g, 11.9 mmol) in THF (5 ml) and the reaction is allowed to stir at room temperature for about 2 h. The reaction is cooled to 0° C. and ice water is added slowly. The mixture is extracted with ethyl acetate, dried over MgSO4, and concentrated. The resulting residue is purified by silica gel column chromatography, eluting with EtOAc/hexanes to afford 2.2 g of the titled compound as a white solid. 1H-NMR.
Reaction SMILES: C1(OC)C=CC=CC=1.COC1C=CC(C[N:16]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([C:26](=[O:40])[C:27]3[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[CH:29][C:28]=3[N+:37]([O-:39])=[O:38])[N:18]=[N:17]2)=CC=1.COC1C=CC(CN2C(C(=O)C3C=C(OC)C(OC)=CC=3[N+]([O-])=O)=C(C(OCC)=O)N=N2)=CC=1>FC(F)(F)C(O)=O>[CH3:36][O:35][C:30]1[C:31]([O:33][CH3:34])=[CH:32][C:27]([C:26]([C:19]2[NH:18][N:17]=[N:16][C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:40])=[C:28]([N+:37]([O-:39])=[O:38])[CH:29]=1
Reactant: CCOC(=O)c1c(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Agent: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nn[nH]c1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 10 h
Yield: 95.2 %

Procedure:
Anisole (1 ml) was added to a solution of an about 1:1 mixture (4.4 g) of ethyl 1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate (Synthesis Example 1, b-1) and ethyl 1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate(Synthesis Example 1, b-2) in trifluoroacetic acid (10 ml), and the mixture was stirred at 60° C. for 10 hr. After the mixture was allowed to stand for cooling, the solvent was evaporated under reduced pressure, followed by azeotropic evaporation using toluene. The resultant crystal was collected by filtration, washed with diethyl ether, and then dried to give ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (3.12 g, 95%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][OH:10])[CH:4]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O>O1CCCC1>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][OH:10])[CH:4]=1
Reactant: N#Cc1ccnc(CO)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccnc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
A solution of 4-cyano-2-hydroxymethylpyridine (0.5 g) in tetrahydrofuran (25 ml) was added dropwise over 20 minutes to a stirred mixture of lithium aluminium hydride (0.25 g) in tetrahydrofuran (30 ml) and the mixture was stirred at room temperature for 2 hours. Wet tetrahydrofuran followed by 0.35 ml of 16% w/w aqueous sodium hydroxide and water were added and the mixture was filtered. The filtrate was evaporated to give crude 4-aminomethyl-2-hydroxymethylpyridine (0.28 g).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>CN(C=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[O:15][CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1c(Br)cccc1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2c(Br)cccc2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.8 %

Procedure:
A solution of 2-benzyl-6-bromophenol (3.2 g, 12.2 mmol) in DMF (50 ml) was treated with K2CO3 (2.19 g, 15.9 mmol) and methyl 4-bromomethylbenzoate (3.21 g, 14.02 mmol). The reaction was stirred at ambient temperature overnight, filtered and partitioned between ethyl acetate and water. The organic phase was washed with water (4×), dried (MgSO4) and evaporated to give methyl 4-(2-benzyl-6-bromophenoxymethyl)benzoate (5.96 g), which was used without further purification. MS(CI+):411(M+H)+
Reaction SMILES: [CH3:1]/[C:2](/[CH:9]=[CH:10]/[CH:11]=[C:12](\[CH3:29])/[CH:13]=[CH:14]/[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([O:22][C:23]([F:26])([F:25])[F:24])=[C:17]([CH3:27])[C:16]=1[CH3:28])=[CH:3]\[C:4](OCC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.CCCCCC>[CH3:1]/[C:2](=[CH:9]\[CH:10]=[CH:11]\[C:12](\[CH3:29])=[CH:13]\[CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([O:22][C:23]([F:24])([F:26])[F:25])=[C:17]([CH3:27])[C:16]=1[CH3:28])/[CH:3]=[CH:4]/[OH:5]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)cc(OC(F)(F)F)c(C)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(/C=C/O)=C\C=C\C(C)=C\Cc1c(C)cc(OC(F)(F)F)c(C)c1C
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Ethyl (2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraenoate could be dissolved in methylene chloride and treated with diisobutylaluminum hydride in hexane solution at -60° C. under argon. The temperature is raised to -10° C. for 10 to 30 minutes and then a saturated solution of magnesium sulfate is added. The mixture is stirred at 25° C. for 2 hours, filtered and evaporated to give (2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraen-1-ol which is further purified by conventional chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][CH:23]([C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)[C:24](O)=[O:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:22][CH:23]([C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)[CH2:24][OH:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(-n2nc(CC(C(=O)O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(CC(CO)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a 3-neck round-bottom flask charged with nitrogen was added 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester (see Method 2, product before hydrolysis; 798 mg, 1.57 mmol, 1.0 equiv) and tetrahydrofuran (6.0 mL). The mixture was cooled to -78° C., then diisobutyl aluminum hydride (4.7 mL, 1.0 M solution in tetrahydrofuran) was added dropwise. The reaction mixture was stirred at −78° C. for 30 min then allowed to warm to room temperature and stirred 1 h. The mixture was then poured slowly into a satd aq solution of Rochelle salt (50 mL). Diethyl ether (50 mL) was added, and the resulting mixture was stirred for 3 h. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford 732 mg of the desired alcohol, which was used in the next step without purification.
Reaction SMILES: CC(C)(C)[C@H](NC1C=CC=C(C(F)(F)F)C=1)C([N:6]1[CH2:11][C@H:10]2[C@H:8]([C:9]2([CH3:13])[CH3:12])[C@H:7]1[C:14]([O:16]C)=[O:15])=O.[OH-].[Na+]>C1COCC1>[CH3:12][C:9]1([CH3:13])[CH:8]2[CH:10]1[CH2:11][NH:6][CH:7]2[C:14]([OH:16])=[O:15]
Reactant: COC(=O)[C@@H]1[C@@H]2[C@H](CN1C(=O)[C@@H](Nc1cccc(C(F)(F)F)c1)C(C)(C)C)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)C2CNC(C(=O)O)C21
Temperature: 25 °C
Reaction time: 3 h
Yield: 251.9 %

Procedure:
(1R,2S,5S)-methyl 3-((S)-3,3-dimethyl-2-(3-(trifluoromethyl)phenylamino)butanoyl)-6,6-dimethyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylate (0.047 g, 0.11 mmol) in THF (1 mL) was added 0.4 N NaOH solution (0.69 mL, 0.28 mmol) and the reaction was stirred at rt for 3 hrs. THF was removed and acidified with saturated KHSO4 until PH=3˜4. The mixture was extracted with Ether (15 mL), washed with brine and dried over sodium sulfate. After removal of solvent, it gave the (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(3-trifluoromethyl)phenylamino)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (0.043 g, 95%) as white solid. MS: Calcd.: 412; Found: [M−H]+ 411.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:28].[NH+]1C=CC=CC=1>C1COCC1>[Br:28][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CCC1
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A mixture of tert-butyl {1-[4-(phenylacetyl)phenyl]cyclobutyl}carbamate (5.0 g, 13.68 mmol, 1.0 eq) and pyridinium hydrobromide perbromide (4.38 g, 13.68 mmol, 1.0 eq) in THF (78 mL) was stirred at 0° C. for 30 minutes. The mixture was partitioned between EtOAc and water, and the organic phase washed with an aqueous sodium thiosulfate solution and brine, dried, filtered through a silicone coated filter paper, and concentrated in vacuo to give the crude title compound (5.44 g, 93% purity by UPLC-MS) which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C(Cl)Cl.CO>[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[N:3]=[N:4][C:5]([CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]([CH3:9])[C:7]=2[CH3:8])=[CH:20][CH:19]=1
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Reactant: Cc1ccc(N)cc1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(Nc2nnc(Cc3ccncc3)c(C)c2C)cc1

Procedure:
The compound is prepared from 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.129 g para-methylaniline in the manner described in Example 82A. Title compound is obtained after FC in CH2Cl2/Methanol 19/1; m.p. 68-70° C. 1H-NMR (250 MHz, CDCl3): δ=8.45 (s, wide, 2H); 7.45 (d, 2H); 7.10 (“d”, wide, 4H); 6.10 (s, wide, 1H); 4.25 (s, 2H); 2.30 (s, 3H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 305 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:34](O)([CH3:36])[CH3:35]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([O:16][CH:34]([CH3:36])[CH3:35])=[O:15])=[CH:10][CH:9]=2)=[CH:20][CH:21]=1
Reactant: CC(C)O
Reactant: CC(Oc1ccc(COc2ccc(Cl)cc2)cc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2)cc1
Reaction time: 4 h
Yield: 64.9 %

Procedure:
6.1 gm of 2-[4-(4-chlorophenoxy-methyl)-phenoxy]-propionic acid was dissolved in 50 ml of absolute tetrahydrofuran, and 3.2 gm of 1,1'-carbonyldiimidazole were added to the solution. The resulting mixture was heated for a short time and was then allowed to stand at room temperature for 4 hours. Thereafter, the reaction mixture was admixed with 2.4 gm of isopropanol, and the mixture was refluxed for one hour, evaporated in vacuo in a rotary evaporator, and the oily residue was recrystallized from ethanol/water, yielding 4.5 gm (65% of theory) of the ester named in the heading, which had a melting point of 81° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>C(#N)C>[CH2:28]([N:30]([CH2:12][C@@H:13]1[O:18][C:17]2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[C:22]([Cl:23])[C:16]=2[O:15][CH2:14]1)[CH2:31][CH3:32])[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCNCC
Solvent: CC#N
Product: CCN(CC)C[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), N-ethylethanamine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 333 (M+, 0.2), 98 (3), 87 (7), 86 (bp), 58 (6), 56 (3).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)([CH2:6][CH3:7])[CH2:4][OH:5].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:35](Cl)=[O:36]>O1CCCC1>[CH3:44][O:43][C:39]1[CH:38]=[C:34]([CH:33]=[C:32]([O:31][CH3:30])[C:40]=1[O:41][CH3:42])[C:35]([O:5][CH2:4][C:3]([N:2]([CH3:1])[CH3:13])([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH2:6][CH3:7])=[O:36]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CCC(CO)(c1cccs1)N(C)C
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(COC(=O)c1cc(OC)c(OC)c(OC)c1)(c1cccs1)N(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
2-Dimethylamino-2-(2-thienyl)-1-butanol (8 g), triethylamine (4.85 g) and dimethylaminopyridine (catalytic amount) are dissolved in tetrahydrofuran (10 ml), and 3,4,5-trimethoxybenzoyl chloride (11.1 g) is gradually added to the solution under ice-cooling. The mixture is stirred at room temperature for 16 hours and concentrated under reduced pressure to remove solvent. The residue is dissolved in diluted hydrochloric acid, and the solution is washed with ether. The solution is alkalized with potassium carbonate and extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and then concentrated under reduced pressure to remove solvent. The residue is purified by silica gel column chromatography (solvent, n-hexane:ethyl acetate=5:2), whereby 2-dimethylamino-2-(2-thienyl)-butyl 3,4,5-trimethoxybenzoate (12.8 g) is obtained as colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccccc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (66 mg, 90%), MS (ISP) m/z=295.5 [(M+H)+], mp 244° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.Br[CH2:15][C:16]#[CH:17]>>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:17][C:16]#[CH:15])=[CH:9][CH:8]=1
Reactant: Oc1ccc(Cc2ncc[nH]2)cc1
Reactant: C#CCBr
Product: C#CCOc1ccc(Cc2ncc[nH]2)cc1

Procedure:
The above compound is prepared in analogy to Example 1 from 4-(1-imidazolylmethyl)-phenol and 1-bromo-2-propyne.