Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18]([OH:20])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([C@H:28]([NH2:30])[CH3:29])=[CH:24][N:23]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=[C:10]([C:18]([NH:30][C@@H:28]([C:25]3[CH:24]=[N:23][C:22]([CH3:21])=[N:27][CH:26]=3)[CH3:29])=[O:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C)nc3)cc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (1.0 g, 3.44 mmol) in N,N-dimethylformamide (10 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (900 mg, 5.58 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (3.0 g, 7.89 mmol) and N,N-diisopropylethylamine (3.0 mL, 17.22 mmol). The reaction mixture was stirred for 16 hours at 25° C. LC-MS indicated the reaction was complete. The reaction solution was diluted with EtOAc and washed with water, sat. aq. NaHCO3, brine and dried over anhydrous MgSO4. The residue was purified by silica gel column and preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[N:9](C2CCCO2)[CH:10]=[CH:11][N:12]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[NH:12][CH:11]=[CH:10][N:9]=1
Reactant: COc1cccc(OCc2nccn2C2CCCO2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(OCc2ncc[nH]2)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
A mixture of 2-(3-methoxy-phenoxymethyl)-1-(tetrahydro-furan-2-yl)-1H-imidazole 1N HCl (20 mL) and THF (20 mL) was stirred at 50° C. for 24 h. Saturated NaHCO3 was added to adjust the pH to 8. The mixture was extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1:2 hexane/EtOAc) to provide the desired 2-(3-methoxy-phenoxymethyl)-1H-imidazole (2.40 g, 92%) as a white solid: ESI MS m/z 205 [C11H12N2O2+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)CC)C.O.[NH2:20][NH2:21]>O>[NH:20]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=1)[NH2:21]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: NN
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)c1ccc(NN)nc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
A suspension of 2-bromo-5-(methanesulfonyl)-pyridine (7.3 g, 116 mmol), triethylamine (14.7 g, 145 mmol), and hydrazine hydrate (7.26 g, 145 mmol) in water (205 mL) was heated to 70° C. The reaction mixture became homogenous before the product started to precipitate out of this mixture (after 90 minutes). The reaction mixture was stirred at 70° C. for total of 5 hours and then was allowed to cool to room temperature and stirred for 18 hours. The precipitated product was collected by filtration, dried and recrystallized from hot ethanol to afford 2-hydrazinyl-5-(methanesulfonyl)-pyridine in 86% yield. Analytical data: 1H NMR (300 MHz, CDCl3) δ 3.12 (s, 3H), 4.44 (br s, 2H), 6.80 (br d, J=8.7 Hz, 1H), 7.81 (dd, J1=9.0 Hz, J2=2.4 Hz, 1H), 8.38 (d, 2.3 Hz, 1H), 8.57 (br s, 1H).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:37])[N:22]([C@@H:24]([C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.ClCCl>[CH3:35][N:33]([CH3:34])[C:32]([C@H:24]([N:22]([CH3:23])[C:21](=[O:37])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:36]
Reactant: CN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)C
Yield: 78.6 %

Procedure:
A solution of N-((1R)-1-(N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylester (6.6 g, 12.8 mmol) in 50% trifluoroacetic acid/dichloromethane (15 ml) was stirred for 10 min. Then saturated sodium bicarbonate was added until pH 8 and the organic phase was separated. The aqueous phase was extracted with dichloromethane (2×20 ml) and the combined organic phases were washed with brine (10 ml), dried over magnesium sulfate and concentrated in vacuo to give 4.2 g of (2R)-N-((1R)-1-dimethylcarbamoyl-2-phenylethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:8][C:7]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:6][C:5]=2[S:4][C:3]=1[CH3:30].C(N(CC)CC)C.Cl.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45](Cl)=[O:46]>>[CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:14][CH:13]=3)=[N:8][C:7]([N:24]3[CH2:25][CH2:26][N:27]([C:45]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=4)=[O:46])[CH2:28][CH2:29]3)=[N:6][C:5]=2[S:4][C:3]=1[CH3:30]
Reactant: Cc1sc2nc(N3CCNCC3)nc(Nc3ccc(N4CCOCC4)cc3)c2c1C
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1sc2nc(N3CCN(C(=O)c4ccccn4)CC3)nc(Nc3ccc(N4CCOCC4)cc3)c2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To 240 mg (1.02 mmol of 2,4-dichloro-5,6-dimethyl-thieno[2,3-d]pyrimidine in 50 ml of ethyl alcohol were added 220.20 mg (1.23 mmol) of 4-(4-morpholino)aniline and 130.90 mg (1.23 mmol) of aniline, and then the mixture was stirred under reflux. After completion of the reaction, the reaction solvent, ethyl alcohol, was evaporated under reduced pressure, and the residue was crystallized from ethyl alcohol and filtered, yielding 430 mg (quantitative) of 2-chloro-5,6-dimethyl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine. 220 mg (0.53 mmol) of the obtained product was dissolved in 20 ml of 1-butanol in a sealed tube, and 223 μl (1.59 mmol) of triethylamine and 45.9 mg of piperazine were added thereto, and the mixture was stirred at 120° C. After completion of the reaction, the resulting solid was filtered and the filtrate was concentrated under reduced pressure and then crystallized from ethyl acetate, yielding 30 mg (15% yield) of 5,6-dimethyl-2-piperazin-1-yl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine. To 9 mg (0.02 mmol) of the obtained compound and 5,6-dimethyl-2-piperazin-1-yl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine in 5 ml of dimethyl chloride were added 3.5 μl (0.02 mmol) of triethylamine and 4.1 mg (0.02 mmol) of picolinoyl chloride hydrochloride, and then the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solvent, dimethyl chloride, was evaporated under reduced pressure, and the residue was crystallized from dimethyl chloride, thus obtaining 6 mg (30% yield) of the title product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:23])=[O:10])[CH2:2]1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30](OB(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[S:15][C:11]([C:9]([NH:8][CH2:7][CH:3]3[O:4][CH2:5][CH2:6][N:1]([C:32]4[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:26]([O:25][CH3:24])=[O:27])[CH2:2]3)=[O:10])=[C:12]([CH3:23])[N:13]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CNCCO1
Product: COC(=O)c1cccc(N2CCOC(CNC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 61.5 %

Procedure:
Using N-(morpholin-2-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (120 mg, 0.341 mmol) and 3-(methoxycarbonyl)phenylboric acid (123 mg, 0.682 mmol), the same procedure was followed as in Example 2 to give 102 mg (62%) of the desired compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].C(N(CC)CC)C.[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][NH2:22]>CC(C)=O>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C@@H:5]([C:6]([OH:8])=[O:7])[NH:22][CH2:21][CH2:20][CH2:19][N:18]([CH3:23])[CH3:17]
Reactant: COC(=O)/C=C\C(=O)O
Reactant: CN(C)CCCN
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)C[C@H](NCCCN(C)C)C(=O)O
Temperature: 25 °C

Procedure:
286 g (2.0 mols+10% excess) of maleic acid-monomethyl ester are placed into a glass flask fitted with a blade stirrer, thermometer, reflux condenser and dropping funnel, and, with ice-water cooling, 400 ml of triethylamine are added dropwise at 6°-11° C. internal temperature within 1 hour and 35 minutes. The cooling is subsequently removed, 204 g (2.0 mols) of 3-dimethylaminopropylamine are quickly added, and the mixture is reacted for 10 minutes at 87°-90° C. and is then cooled to room temperature; the crystalline crude product is mixed with 1 liter of acetone, the suspension is filtered, and the filter residue is washed with acetone. The yield after drying at 80° C. in vacuo is 296 g (63.7% of theory) of a crystalline aspartic acid derivative, which melts at 171°-172° C.
Reaction SMILES: C[C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]3[C:29]([CH2:30][N:31]4[CH:35]=[CH:34][CH:33]=[N:32]4)=[CH:28][C:27]4[C:26]([CH3:37])([CH3:36])[CH2:25][CH2:24][C:23]([CH3:39])([CH3:38])[C:22]=4[CH:21]=3)=[CH:14][CH:13]=2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O-:7])=[O:6].Cl>[Li+].[OH-].C(O)C>[CH3:36][C:26]1([CH3:37])[CH2:25][CH2:24][C:23]([CH3:38])([CH3:39])[C:22]2[CH:21]=[C:20]([CH2:19][CH2:18][C:15]3[CH:16]=[CH:17][C:12]([O:11][C:3]4[CH:2]=[CH:10][CH:9]=[CH:8][C:4]=4[C:5]([OH:7])=[O:6])=[CH:13][CH:14]=3)[C:29]([CH2:30][N:31]3[CH:35]=[CH:34][CH:33]=[N:32]3)=[CH:28][C:27]1=2
Reactant: Cc1cccc(C(=O)[O-])c1Oc1ccc(CCc2cc3c(cc2Cn2cccn2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(Cn3cccn3)c(CCc3ccc(Oc4ccccc4C(=O)O)cc3)cc21
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A solution of 0.131 g (0.293 mmol) of Methyl-4-[2-(5,5,8,8-tetramethyl-3-(pyrazol-1-ylmethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]phenoxybenzoate in 3 ml 1M LiOH and 10 ml ethyl alcohol was heated to reflux. After 2 hours the reaction was cooled to room temperature and acidified with 1M hydrochloric acid. The aqueous layer was extracted with ethyl ether, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (gradient elution with 10% methanol/dichloromethane-10% methanol/dichloromethane with 5% acetic acid) to afford 0.101 g (79%) of 4-[2-(5,5,8,8-tetramethyl-3-((pyrazol-1-yl)methyl)-5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]phenoxy benzoic acid (M+1=433).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2
Reactant: Cc1ccc2c(Cl)ccnc2c1
Reactant: Cc1ccc2[nH]c(C)cc2c1
Product: Cc1ccc2c(-c3c(C)[nH]c4ccc(C)cc34)ccnc2c1

Procedure:
The sub-title compound was prepared by the method of Example 1 step a) using 2,5-dimethyl indole and 4-chloro-7-methyl-quinoline.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:9]=[C:8]([CH:22]=[CH2:23])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH2:26])=[N-]>C(OCC)C.C(O)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:22]1([C:8]2[CH:9]=[C:10]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:11]=[C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)[CH2:26][CH2:23]1
Reactant: C=Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Nc1ccc(S(=O)(=O)c2cc(C3CC3)nc(N3CCCC3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
0.165 g (0.0005 Mol) 4-(2-Pyrrolidin-1-yl-6-vinyl-pyridine-4-sulfonyl)-phenylamine were dissolved in ethyl ether (100 ml) and cooled to 0° C. A solution of diazomethane in ethyl ether (30 ml) was carefully added. Upon addition of a catalytic amount of Pd(OAc)2 gas evolution started. The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. After addition of a few drops of acetic acid the solvent was evaporated and the residue chromatographed on SiO2 with ethyl acetate hexane 1:2. It was obtained 0.149 g (87%) of 4-(2-cyclopropyl-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine as bright yellow cristals; mp.: 216-218° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:32]#[C:31][CH2:30][CH2:29][OH:33])[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: C#CCCO
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Product: OCCC#Cc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Yield: 81 %

Procedure:
Following the procedures for 246, 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene and but-3-yn-1-ol were reacted under palladium catalysis to give 4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-but-3-yn-1-ol (Yield: 81%. 1H NMR (DMSO-d6, 400 MHz): δ8.31 (s, 1H), 7.94-7.88 (m, 1H), 7.74-7.68 (m, 1H), 7.43-7.38 (m, 2H), 7.31 (d, J=8.4 Hz, 1H), 6.92 (s, 1H), 4.95 (s, 1H), 4.31 (t, J=4.0 Hz, 2H), 3.62 (m, 2H), 3.12 (t, J=4.4 Hz, 2H), 2.61 (t, J=6.8 Hz, 2H). LC-MS (ESI): m/z=451 [M+H]+), which was hydrogenated to give 245 Yield: 43%. 1H NMR (DMSO-d6, 400 MHz): δ8.27 (s, 1H), 7.90-7.84 (m, 1H), 7.70-7.65 (m, 1H), 7.41-7.39 (m, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.99 (s, 1H), 4.37 (s, 1H), 4.23 (t, J=4.8 Hz, 2H), 3.40 (t, J=6.4 Hz, 2H), 3.09 (t, J=4.8 Hz, 2H), 2.64-2.60 (m, 2H), 1.65-1.59 (m, 1H), 1.44-1.38 (m, 1H). LC-MS (ESI): m/z=455 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][N:25]([CH3:29])[C:26](=[O:28])[CH3:27])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:30])[CH3:9])=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1>>[CH3:29][N:25]([CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:30])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:36]3[CH:35]=[CH:34][N:33]=[C:32]([CH3:31])[CH:37]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)[C:26](=[O:28])[CH3:27]
Reactant: CC(=O)N(C)CCC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: Cc1cc(B(O)O)ccn1
Product: CC(=O)N(C)CCC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccnc(C)c3)cc2)C(=O)O1

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylacetamide and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.98, m/z=486.2; 1H NMR (CDCl3) 1.21-1.38 (m, 1H), 1.52 (d, 3H), 1.61-1.90 (m, 3H), 2.05 (d, 3H), 2.17 (m, 1H), 2.42 (m, 2H), 2.78 (s, 1H), 2.83 (s, 3H), 2.85 (s, 2H), 2.92 (m, 1H), 3.11-3.33 (m, 2H), 5.65 (m, 1H), 7.05 (d, 2H), 7.21 (m, 2H), 7.30 (m, 3H), 7.38 (d, 2H), 7.60 (s, 1H), 7.71 (d, 1H), 8.72 (d, 1H).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[OH:39][CH2:38][CH2:37][NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NCCO)c1
Product: O=C(Nc1cccc(S(=O)(=O)NCCO)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2-hydroxy-ethyl)-benzenesulfonamide [CAS 436095-41-9] according to general procedure II. Light yellow solid. MS (ISP) 554.0 [(M−H)−]; mp 231° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([OH:9])=[O:8].CCN(C(C)C)C(C)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20]([N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[C@H:3]1[C:7]([OH:9])=[O:8])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)[C@H]1NCC[C@@H]1O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1[C@@H](O)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
(2S,3S)-3-Hydroxy-pyrrolidine-2-carboxylic acid (254.5 mg, 1.9 mmol) was dissolved in DMF (15 mL) and distilled water (6 mL). The solution was cooled to 0° C., and DIEA (500 μL, 2.9 mmol) was added followed by benzyl chloroformate (410 μL, 2.9 mmol). The reaction was stirred at 0° C. and allowed to warm to ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([C@@H:25]([CH3:27])[OH:26])[NH:5][C:6](=[O:24])[C@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>[OH-].[K+]>[C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:28])=[O:2])[C@@H:25]([CH3:27])[OH:26])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: COC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)[C@@H](C)O
Agent: [K+]
Agent: [OH-]
Product: C[C@@H](O)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
19.6 Grams of Boc-L-tyrosyl-L-threonine methyl ester are dissolved in 75 ml of 2 M potassium hydroxide solution at room temperature. After 30 minutes the aqueous solution is extracted with 20 ml of ethyl acetate, acidified with cold 1 M potassium bisulfate, and extracted with four 25 ml portions of ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and filtered. The solvent is removed under reduced pressure to give Boc-L-tyrosyl-L-threonine.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=4)[CH2:13]3)[C:9]2=[O:27])[CH2:4][CH2:3]1.CO>>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C:10]3([C:9](=[O:27])[N:8]([C@H:5]4[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]4)[CH2:12][CH2:11]3)[CH2:13]2)=[CH:19][CH:20]=1
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCCN(c1ccc([N+](=O)[O-])cc1)C2
Solvent: CO
Product: Nc1ccc(N2CCCC3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)cc1
Reaction time: 1.5 h

Procedure:
A mixture of 2-(trans-4-hydroxycyclohexyl)-7-(4-nitrophenyl)-2,7-diazaspiro[4.5]decan-1-one (0.13 g, 0.00028 mol, prepared by using a procedure that was analogous to that described for the synthesis of example 43), 10% PdC (activated) in methanol (5 mL, 0.1 mol) was stirred under a H2 atmosphere (balloon) for 1.5 hour. The catalyst was filtered and the filtrate was concentrated in-vacuo to afford the desired product in quantitative yield. LC-MS: 344.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][CH2:26][CH2:25][C:24]=3[CH:28]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:32])=O>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:32])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][CH2:26][CH2:25][C:24]=3[CH:28]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1[nH]c(=O)c2ccc(Oc3ccc4c(c3)CCO4)cc2c1O
Product: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc4c(c3)CCO4)cc2c1O

Procedure:
Prepared in analogy to example 31f from 6-(2,3-dihydro-benzofuran-5-yloxy)-4-hydroxy-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester and POBr3. ESI MS (m/z): 458 (M+H)+.
Reaction SMILES: [N+]([O-])(O)=O.OS(O)(=O)=O.[CH3:10][C:11]1C=C(C=CC=1)C(O)=O.CC1C([N+]([O-])=O)=C(C([N+]([O-])=O)=CC=1)C(O)=O.[CH3:36][C:37]1[C:38]([N+:49]([O-:51])=[O:50])=[CH:39][C:40]([N+:46]([O-:48])=[O:47])=[C:41]([CH:45]=1)[C:42]([OH:44])=[O:43].O=S(Cl)Cl>CCO>[CH3:36][C:37]1[C:38]([N+:49]([O-:51])=[O:50])=[CH:39][C:40]([N+:46]([O-:48])=[O:47])=[C:41]([CH:45]=1)[C:42]([O:44][CH2:10][CH3:11])=[O:43]
Reactant: Cc1cc(C(=O)O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Cc1cccc(C(=O)O)c1
Agent: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 25.4 %

Procedure:
To a mixture of HNO3 (95%, 80 mL) and H2SO4 (98%, 80 mL) was slowly added 3-methylbenzic acid (50 g, 0.37 mol) at 0° C. After addition, the mixture was stirred below 30° C. for 1.5 hours. The mixture was then poured into ice-water and stirred for 15 min. The precipitate solid was filtered and washed with water to give a mixture of 3-methyl-2,6-dinitro-benzoic acid and 5-methyl-2,4-dinitrobenzoic acid (70 g, 84%). To a solution of this mixture (70 g, 0.31 mol) in EtOH (150 mL) was added dropwise SOCl2 (54 g, 0.45 mol). The mixture was heated at reflux for 2 h before being concentrated to dryness under reduced pressure. The residue was partitioned between EtOAc (100 mL) and aq. Na2CO3 (10%, 120 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated to dryness to obtain ethyl 5-methyl-2,4-dinitrobenzoate (20 g), which was placed aside. The aqueous layer was acidified by HCl to pH 2˜3 and the precipitated solid was filtered, washed with water, and dried in air to give 3-methyl-2,6-dinitrobenzoic acid (39 g, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10](O)=[O:11])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([Cl:16])=[O:11])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(C)C(=O)O)cc1
Product: COc1ccc(C(C)C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
Under an argon atmosphere, 2-(4-methoxyphenyl)propanoic acid (synthesized by the process of I. Shiina, et al., Eur J. Org. Chem., 5887-5890 (2008)) (1.20 g, 6.66 mmol) was dissolved in thionyl chloride (6.00 mL, 82.6 mmol) and the solution was heated to reflux for 27 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give the crude product of 2-(4-methoxyphenyl)propanoyl chloride (16) as a colorless oil. The product was used in the following reaction without further purification.