Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](C#N)=[N:6][CH:7]=1.[CH3:10][Mg]Br.Cl.[C:14](=[O:17])(O)[O-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:14](=[O:17])[CH3:10])=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=C([O-])O
Reactant: N#Cc1ccc(F)cn1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(F)cn1
Temperature: -64 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
5-Fluoro-pyridine-2-carbonitrile (29 g, 240 mmol) was dissolved in THF (150 mL) under a nitrogen atmosphere. The reaction mixture was cooled to an internal temperature of −64° C. Methyl magnesium bromide (3M in THF, 105 mL, 315 mmol) was added over 40 min. The reaction mixture was stirred at −65° C. for 1.5 h, then warmed to room temperature. THF (50 mL) was added and the mixture was stirred an additional 3 h. 2M hydrochloric acid (aq., 100 mL) was added until the mixture was slightly acidic and the reaction mixture was stirred at room temperature over night. Sodium bicarbonate was then added to neutralize the reaction mixture. The phases were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with Brine, dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash column chromatography to yield 18 g (55% yield) of the title compound.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:34]=[CH:33][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][C:25]([C:28]([O:30]CC)=[O:29])([CH3:27])[CH3:26])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:35][C:2]([F:1])([F:36])[C:3]1[CH:34]=[CH:33][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][C:25]([C:28]([OH:30])=[O:29])([CH3:27])[CH3:26])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)(C)Oc1cc(C2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)cc1OC(C)(C)C(=O)O
Temperature: 25 °C
Yield: 93.5 %

Procedure:
A mixture of 3-[3-(1-ethoxycarbonyl-1-methyl-ethoxy)-4-methyl-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester (156 mg, 0.31 mmol), potassium carbonate (85 mg, 0.62 mmol), methanol (10 mL) and water (2 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 139 mg (94%) of 3-[3-(1-carboxy-1-methyl-ethoxy)-4-methyl-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a white solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:34])[NH:10][C@@H:11]([CH2:27][C:28]2[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:19]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]3[O:7][C@@H:6]3[C:4]([OH:5])=[O:3])=[O:34])[CH2:27][C:28]3[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=3)[S:16][CH:17]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cncn1C)C(=O)Nc1nc(-c2ccc(F)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1cncc1C[C@H](NC(=O)[C@H]1O[C@@H]1C(=O)O)C(=O)Nc1nc(-c2ccc(F)cc2)cs1
Yield: 46.9 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 20 (129 mg, 0.26 mmol): LiOH (6.3 mg, 0.26 mmol); THF/MeOH/H2O (2.5 mL: 1.5 mL: 1.5 mL); yielded 35 as a white solid (56 mg, 46.1%). 1H NMR (DMSO-d6, 400 MHz): 8.92-8.90 (d, 1H); 7.96-7.91 (m, 2H): 7.68 (s, 1H); 7.35-7.24 (m, 3H); 4.94-4.87 (m, 1H); 4.64-4.56 (m, 2H); 3.82-3.50 (m, 5H). 13C NMR (400 MHz, DMSO-d6): 171.52, 167.50, 165.57, 162.45, 161.02, 148.42, 138.62, 131.27, 128.18, 128.01, 127.83, 127.05, 116.17, 115.99, 106.70, 53.24, 52, 58, 51.90, 31.29, 29.52. ESI-HRMS (m/z): [M+H+] calcd. for C20H18FN5O5S: 460.1085; observed, 460.1092; Rt=17.8 min, purity=93.6%.
Reaction SMILES: [CH2:1]([N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]1=[O:12])[C:2]#[CH:3].[C:13]1([N:19]=[N+:20]=[N-:21])[CH:18]=[CH:17]C=CC=1.CCN(C(C)C)[CH:25]([CH3:27])[CH3:26]>C1COCC1.C(Cl)Cl.[Cu]I>[C:1]1([N:4]2[CH:9]=[CH:8][C:7]([CH2:17][C:18]3[N:21]=[N:20][NH:19][CH:13]=3)=[C:6]([O:10][CH3:11])[C:5]2=[O:12])[CH:27]=[CH:25][CH:26]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Reactant: C#CCn1cccc(OC)c1=O
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1c(Cc2c[nH]nn2)ccn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
150 (0.32 g, 1.951 mmol) and phenylazide (0.348 g, 2.926 mmol) were dissolved in anhydrous THF (10 mL) and stirred under argon at room temperature. Copper (I) iodide (0.011 g, 0.07 mmol) and Hunig's base (0.1 mL) were then added to the reaction mixture, and stirring continued for 4 h. The reaction mixture was diluted with CH2Cl2 (40 mL) and washed with 1:4 NH4OH/saturated NH4Cl (3×30 mL) and saturated NH4Cl (30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was triturated with hexanes to give 510 mg (92%) of white solid 151a. 1H NMR (CDCl3, 400 MHz) δ 3.58 (3H, s), 5.11 (2H, s), 5.93 (1H, t, J=7.6), 6.42 (1H, d, J=7.2), 7.07 (1H, d, J=6.4), 7.16-7.20 (1H, m), 7.26 (2H, t, J=7.6), 7.49 (2H, d, J=8.0); 13C NMR (CDCl3, 100 MHz) δ 44.2, 55.2, 104.7, 112.0, 119.7, 121.8, 127.9, 128.1, 129.0, 136.2, 142.8, 149.3, 157.2. HRMS (EI) calcd for C15H14N4O2 [M]+ 282.1117. found 282.1115.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[O:23])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), morpholine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N#N.C([Li])CCC.C[O:24][B:25](OC)[O:26]C>C1COCC1>[C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([B:25]([OH:26])[OH:24])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc(C#Cc2ccccc2)cc1
Reactant: COB(OC)OC
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(C#Cc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 65.5 %

Procedure:
In a flame-dried flask, 4-(phenylethynyl)-1-bromobenzene (15.0 g, 58.4 mmol) was dissolved in dry THF (225 mL). The solution was treated with 3 cycles of evacuation and refilling with N2, then chilled to −78° C. in a dry ice/acetone bath. To the stirred solution was added a solution of n-butyllithium in hexanes (1.6 M, 40 mL, 1.1 eq) by syringe over the course of 10 minutes. The resulting solution was stirred for an additional 30 minutes before trimethylborate (9.77 mL, 9.1 g, 1.5 eq) was added slowly over 15 minutes. After stirring for an additional 15 minutes, the cooling bath was removed and the solution was allowed to warm to room temperature and stir for 16 h. At this time, 2 M HCl (aqueous) (375 mL) was added, and the biphasic system was stirred vigorously for 2 hours. Ethyl acetate was added, and the organic layer was separated, dried (MgSO4), filtered and evaporated. Methylene chloride (100 mL) was added to the solid residue, which was crushed and mixed into a paste, then filtered and washed with additional portions of methylene chloride to give 8.5 g of the title compound as a white powder.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:8][CH:7]=1.O.O.[Cl:22][Sn]Cl>O.[OH-].[Na+].Cl>[ClH:22].[NH:5]([C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:8][CH:7]=1)[NH2:1]
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Reactant: Nc1ccc(S(=O)(=O)O)c2c1CCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1ccc(S(=O)(=O)O)c2c1CCCC2
Temperature: 5 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
1 g of NaNO2 is added to a solution of 3 g of the acid obtained in step A in 10 ml of water and 2 ml of 30% sodium hydroxide. This solution is poured over 1 hour into 10 ml of concentrated HCl cooled to 5° C. After stirring for 3 hours at 5° C., a solution of 7.5 g of SnCl2.2H2O in 15 ml of concentrated HCl is added slowly while the temperature is maintained at 5° C. The mixture is left stirring for one and a half hours at RT and filtered, and the residue is dried under vacuum to obtain 2.86 g of the expected product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[CH2:9][N:10]2C(OC(C)(C)C)=O.[F:21][C:22]([F:27])([F:26])[C:23]([O-:25])=[O:24]>>[OH:25][C:23]([C:22]([F:27])([F:26])[F:21])=[O:24].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[CH2:9][NH:10]2
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccccn1
Reactant: O=C([O-])C(F)(F)F
Product: O=C(O)C(F)(F)F
Product: c1ccc(N2C[C@@H]3C[C@H]2CN3)nc1

Procedure:
This compound was synthesized from (1S,4S)-tert-butyl 5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as described for example 46 step 4 (50 mg, crude) as trifluoroacetate salt and it was taken as such for the next step. MS (ESI) m/z: Calculated for C10H13N3: 175.11. found: 175.9 (M+H)+
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][C:13]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])=[CH:14][N:15]=1)([CH3:10])[CH3:9].C1(C)C=CC=CC=1>C(Cl)Cl>[CH:8]([C:11]1[S:12][C:13]([C:16]([N:18]2[CH2:23][C:22]3([CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)[O:21][CH2:20][CH2:19]2)=[O:17])=[CH:14][N:15]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ncc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ncc(C(=O)N2CCOC3(CCNCC3)C2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (3.9 mL) was added to a solution of tert-butyl 4-(2-isopropylthiazole-5-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 113, step a) (0.765 g) in DCM (14.8 mL). The resulting mixture was stirred at RT for 1 h. Toluene (30 mL) was added and the mixture was evaporated in vacuo. The yellow residue was dissolved in MeOH and applied to a SCX cartridge pre-wetted with MeOH. The cartridge was washed with MeOH and eluted with 2M ammonia in MeOH. The eluent was evaporated in vacuo to give the subtitled compound as a yellow oil. Yield 0.552 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Li]CCCC.[CH3:18][C:19]1[C:20](=O)[CH:21]([CH3:26])[CH:22]([CH3:25])[C:23]=1[CH3:24].Cl>C1COCC1>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([C:20]3[CH:19]([CH3:18])[C:23]([CH3:24])=[C:22]([CH3:25])[C:21]=3[CH3:26])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1ccc2cccc(Br)c2n1
Reactant: CC1=C(C)C(C)C(C)C1=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C(C)C(c2cccc3ccc(C)nc23)=C1C
Temperature: 25 °C
Yield: 60.7 %

Procedure:
A solution of 4.4 g of 8-bromo-2-methylquinoline (20 mmol) in 50 ml of THF was cooled to −78° C., and 8.8 ml of n-BuLi (2.5 M in hexane, 22 mmol) was added dropwise while stirring. After ten minutes of stirring, 3.5 g of 2,3,4,5-tetramethylcyclopentenone (25 mmol) was added dropwise; the solution was heated to room temperature and then heated in reflux for one hour. The solution was cooled down; ice and hydrochloric acid to approximately pH 1 were added; and after neutralization with ammonia solution, the phases were separated and the aqueous phase was extracted with pentane. The combined organic extracts were dried, the pentane was removed in a vacuum, and the remaining brown oil was distilled in a high vacuum (boiling point: 115° C. at 0.01 mbar). A 60% yield (3.2 g) of 1-(2-methyl-8-quinolyl)-2,3,4,5-tetramethylcyclopentadiene in the form of yellow, viscous oil was obtained.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12](O)=[O:13])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.CO>[C:1]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][OH:13])[C:8]=2[C:15]([F:17])([F:18])[F:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1noc(-c2ccccc2)c1C(F)(F)F
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: OCc1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
To a solution of 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (Intermediate 1-5D, 3.0 g, 11.7 mmol) in THF (20 mL) at 0° C. was added N-methylmorpholine (1.92 mL, 17.5 mmol) followed by isobutyl chloroformate (2.30 mL, 17.5 mmol) via syringe over 5 min. The resulting suspension was stirred at 0° C. for 15 min. The suspension was then added to a suspension of sodium borohydride (0.794 g, 21.0 mmol) in THF (40 mL) and methanol (12 mL) at −78° C. via a 10 mL syringe. During the addition, frothing was observed. The reaction mixture was stirred for 60 min. The reaction mixture was slowly warmed to approximately −20° C. and quenched with a 20 mL of a 1:9 mixture of acetic acid in water. The reaction mixture was then stirred at room temperature for 60 min. The solvent was removed under reduced pressure, and the residue was diluted with ethyl acetate (120 mL), washed with water (20 mL), saturated aqueous solution of sodium bicarbonate (2×20 mL) and brine (20 mL). The organic layer was collected, the aqueous layers were back-extracted with ethyl acetate (100 mL), and the combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture of ethyl acetate in hexane (1% to load; 5%-9%-12%) afforded (5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)methanol (1.79 g, 7.36 mmol, 63% yield) as a clear, colorless oil. The compound had an HPLC ret. time=2.02 min. (condition A); LC/MS M+1=243.8.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9][C:10]1[C:11]2[NH:27][CH:26]=[CH:25][C:12]=2[N:13]=[C:14]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:15]=1.C1C(=O)N([Cl:36])C(=O)C1>C(Cl)Cl>[Cl:36][C:25]1[C:12]2[N:13]=[C:14]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[N:15]=[C:10]([S:9][C:2]3[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=3[CH3:28])[C:11]=2[NH:27][CH:26]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3cc[nH]c23)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3c(Cl)c[nH]c23)c(C)c1
Yield: 104.8 %

Procedure:
To a solution of 4-(4-(mesitylthio)-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino)benzonitrile (10 mg, 0.02 mmol) in CH2Cl2 (5 mL) was added NCS (2.8 mg, 0.02 mmol) and the resolution mixture refluxed for 16 h. After the completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with hexanes:ethyl acetate (3:1), to give the product (8.8 mg, 88%).
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[NH2:9][CH2:10][CH:11]1[O:15][CH2:14][CH:13]([S:16][C:17]2[CH:23]([CH3:24])[CH:22]3[N:19]([C:20](=[O:28])[CH:21]3[CH:25]([OH:27])[CH3:26])[C:18]=2[C:29]([OH:31])=[O:30])[CH2:12]1.C(O[CH:36](OC(C)C)[N:37]([CH3:39])[CH3:38])(C)C>>[CH3:36][N:37]([CH:39]=[N:9][CH2:10][CH:11]1[O:15][CH2:14][CH:13]([S:16][C:17]2[CH:23]([CH3:24])[CH:22]3[N:19]([C:20](=[O:28])[CH:21]3[CH:25]([OH:27])[CH3:26])[C:18]=2[C:29]([OH:31])=[O:30])[CH2:12]1)[CH3:38]
Reactant: CC(C)OC(OC(C)C)N(C)C
Reactant: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN)C3)C(C)C12
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN=CN(C)C)C3)C(C)C12
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
Three ml of sodium phosphate buffer, pH 7, is cooled to 0° C. and 0.052 g of product from Example 46 is added. To this cooled solution is added, dropwise, 159 μl of N,N-dimethylformamide diisopropyl acetal, while maintaining the pH below 8.5. The reaction mixture is stirred at 0° C. for 35 minutes, pH adjusted to 7.0 and freeze-dried. The residue is purified by chromato-graphy (c18 reverse phase tlc plates: 75% aqueous ethyl alcohol) to give 0.031 g of the desired product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[C:8]([Mg]Br)#[CH:9].P([O-])(O)(O)=O.[Na+]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:7])[C:8]#[CH:9]
Reactant: O=Cc1ccco1
Reactant: C#C[Mg]Br
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(O)c1ccco1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2 g of 2-furaldehyde in 30 ml of tetrahydrofuran were cooled to 0° C. and 50 ml of a 0.5M solution of ethynyl magnesium bromide in tetrahydrofuran were added dropwise over 15minutes. The mixture was stirred for 1 hour at 0° C., poured into a saturated aqueous sodium dihydrogenphosphate solution and extracted with isopropyl ether. The extract was dried and the solvent was evaporated to obtain 2.5 g of the expected product after chromatography on silica (eluent: 75/25 hexane/ethyl acetate).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:25])[C@H:6]([CH2:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=1[CH3:24])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1.C(OCC)(=O)C>C(Cl)Cl.O>[CH3:3][O:4][C:5](=[O:25])[C@H:6]([CH2:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)=[CH:18][C:17]=1[CH3:24])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: COC(=O)[C@H](Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c(C)cc(OCc2ccc(C#N)cc2)cc1C)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A dispersion of NaH in oil (27.3 mmol) was weighed into a 11 round bottom flask containing a magnetic stirrer. The dispersion was washed with hexane to remove the mineral oil, and the flask was immediately charged with tetrahydrofuran (THF) (200 ml). Boc-2,6-dimethyltyrosine methylester (Example 29, 8 g, 24.8 mmol) was added and a drying tube was inserted The mixture was stirred for 2 hr. α-Bromo-p-toluonitrile (5.24 g, 26.8 mmol) was then added, and the mixture stirred at room temperature overnight. A thin layer chromotogram (2:1 Skelly B: Ethyl Acetate) was then run. If starting material was still present, NaH dispersion (1/2 molar amount) and alkylating agent (1/2 molar amount) were added and the reaction run another 24 hr at room temperature. The mixture was then poured into water (1.21) and rapidly extracted thrice with CH2Cl2. The organic fractions were combined, dried (MgSO4), and stripped to give a product (O-(p-cyanobenzyl)-Boc-2,6-dimethyltyrosine methyl ester) which was directly hydrolyzed with NaOH as described in Example 1 to give the title compound. NMR: benzyl methylene ∫5.10 s; tyrosyl aromatic protons ∫6.60s; benzyl aromatic protons centered at ∫7.65.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.CCO.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=O.N#N>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:17]([CH:18]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C=O
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Agent: N#N
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1NCCc2c1[nH]c1ccccc21
Yield: 66.6 %

Procedure:
2,3,4,9-Tetrahydro-1H-betacarboline-1-carboxylic acid ethyl ester was prepared by the addition of tryptamine-HCl (1.33 g, 6.76 mmol), EtOH (12 mL), and a 50% toluene solution of ethyl glyoxylate (1.66 g, 8.11 mmol) to a 50 mL flask purged with N2. The reaction solution was allowed to reflux 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude material was chromatographed (SiO2, 100% DCM to 4% MeOH) to provide 1.10 g (68% yield) of 2,3,4,9-tetrahydro-1H-betacarboline-1-carboxylic acid ethyl ester; 1H NMR (CDCl3) δ 8.59 (1H, br s), 7.46 (1H, d), 7.39 (1H, d), 7.23 (1H, t), 7.14 (1H, t), 5.40 (1H, s), 4.24 (2H, q), 3.51 (1H, m), 3.07 (1H, m), 2.86 (1H, d), 1.30 (3H, t); 13C NMR (CDCl3) δ 166, 137, 126, 123, 122, 120, 119, 112, 108, 64, 60, 53, 41, 14; MS (ESI): 245 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1[O:20][CH2:19]1>C(O)(=O)C>[CH2:1]([N:8]([CH2:18][CH2:19][OH:20])[C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CO1
Reactant: NC(=O)c1ccccc1NCc1ccccc1
Solvent: CC(=O)O
Product: NC(=O)c1ccccc1N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
o-Benzylaminobenzamide (62 g) was added to a cold solution of 85 ml ethylene oxide in 500 ml acetic acid, the mixture stirred 22 hours at room temperature and concentrated on the rotovap to remove 250 ml acetic acid. The remainder was made alkaline with 10% NaOH and the solid filtered washed with water and recrystallized from 300 ml ethyl acetate to give 48.5 g. product, m. 133-7.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:13](=[S:41])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=S)c2-c2ccc(F)cc2)cc1
Yield: 88 %

Procedure:
A mixture of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared according to the method of Example 5, (109 mg, 0.25 mmol) and Lawesson's reagent (202 mg, 0.5 mmol) in 15 mL of toluene was stirred at reflux for 48 hours. The mixture was concentrated in vacuo and the residue was chromatographed (silica gel, ethyl acetate) to provide the title compound (yield: 100 mg, 88%). mp 88-90° C. 1H NMR (300 MHz, CDCl3) δ 3.04 (s, 3H), 6.05 (s, 2H), 6.96 (m, 2H), 7.08 (m, 2H), 7.26 (m, 2H), 7.37 (m, 3H), 7.61 (m, 2H), 7.84 (d, J=9 Hz, 2H), 8.13 (s, 1H). MS (DCI/NH3) m/z 451 (M+H)+.